Methods of treating ankylosing spondylitis using il-17 antagonists

ABSTRACT

The disclosure relates to novel regimens for treating an inflammatory arthritis, e.g., psoriatic arthritis, which employ a therapeutically effective amount of an Interleukin-17 (IL-17) antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen binding fragment thereof).

TECHNICAL FIELD

The disclosure relates to novel methods for treating arthritis, whichemploy a therapeutically effective amount of an IL-17 binding molecule,e.g., an IL-17 antibody, such as the AIN457 antibody (which is alsoknown as “secukinumab”).

BACKGROUND OF THE DISCLOSURE

Rheumatoid arthritis (RA) is a chronic, inflammatory, systemicautoimmune disease of unknown etiology. It is characterized by symmetricsynovitis leading to cartilage damage and joint destruction and can becomplicated by numerous extra-articular manifestations. Given thepresence of autoantibodies, such as rheumatoid factor (RF) andanti-citrullinated protein antibody (ACPA), RA is considered anautoimmune disease. RA is generally a progressive disease withfunctional status decline, significant morbidity and premature mortalityseen in established RA. The disease can occur at any age, with a peakincidence between the fourth and sixth decades. The goal of long-term RAtreatment is disease remission.

Disease-modifying antirheumatic drugs (DMARDs), a heterogenouscollection of agents grouped by use and convention, are the first lineof treatment for RA patients. DMARDs are used to reduce joint swellingand pain, decrease acute-phase markers, limit the progression of jointdamage and to improve joint function. DMARDs, most often methotrexate(MTX), are prescribed upon disease diagnosis (i.e., early RA), usuallybefore the development of erosive disease and the deformities seen inestablished RA. MTX therapy is initiated if pain and synovitis persist(especially if function is compromised), and additional DMARDs (with orwithout steroids) may be added to achieve disease control.Unfortunately, only about ⅔ of patients respond to DMARDS, and DMARDsonly partially control established RA disease. Radiological progressioncontinues even in the 5-20% of DMARD-treated RA patients that achieveremission or clinical improvement that approaches remission. DMARDS alsohave many adverse effects (e.g., liver damage, bone marrow suppressionand severe lung infection) that limit their prolonged use.

Due to the inadequate responses and dangers associated with prolongedDMARD treatment, biologics have been introduced as second line RAtreatments. In general, anti-TNF agents (Cimzia®, Enbrel®, Humira®,Remicade®, Simponi®) are the first biologics used in DMARD-failure andDMARD-inadequate responder patients, and a TNF inhibitor is oftencombined with MTX (or another DMARD) to aggressively treat establishedRA. Unfortunately, 30-40% of patients with established RA fail torespond to TNF-α antagonists and the majority of those that respondinitially do not achieve complete remission or lose response over time.Concerns have also been raised about the short and long-termtolerability and safety of chronic biologic treatment, most notably thereactivation of serious infections (e.g., tuberculosis infections),liver toxicity, increased cardiovascular disease, induction (orexacerbation of) demyelinating conditions, and increased incidence ofmalignancy due to TNF-alpha antagonisim. M. Khraishi (2009) J. RheumatolSuppl. 82:25-32; Salliot et al. (2009) Ann. Rheum. Dis. 68:25-32.However, a TNF inhibitor is usually continued unless it becomesineffective or an adverse event arises, at which point a clinician mayswitch to either a different TNF inhibitor or a biological with adifferent mechanism of action (e.g., Kineret® [IL-1R antagonist],MabThera® [CD20 antagonist], Orencia® [CTLA4 fusion protein] or Actemra®[IL-6 receptor antagonist]). Scott et al. (2010) The Lancet376:1095-1108.

Given the aforementioned problems with current RA therapy, there is aneed to develop new treatments for RA patients.

SUMMARY OF THE DISCLOSURE

Secukinumab, a new biological in clinical development for RA, is ahigh-affinity fully human monoclonal anti-human antibody that inhibitsInterleukin-17A activity. In an RA proof-of-concept (PoC) study,patients with active RA who were on a stable dose of MTX were dosed inrising single and then 2 doses (21 days apart) with secukinumab at 1mg/kg, 3 mg/kg and 10 mg/kg intravenously. Hueber et al. (2010) Sci.Transl. Med. 2(52):52-72. Treatment with secukinumab resulted in rapidimprovement of the clinical manifestations of RA in many patientscompared to placebo. These data provide evidence that neutralization ofIL-17A is likely to be efficacious in RA patients with active RA.However, since patient response to biological treatment is variable andit is desirable to avoid providing drug to patients who will beresistant thereto, we have sought methods of treating RA that firstidentity those patients most likely to respond favorably to antagonismof IL-17. We have identified an RA subgroup having patients that displayan improved likelihood of responding to IL-17 antagonism, whom we havenamed “high risk RA patients”.

Thus, it is one object of the disclosure to provide methods ofidentifying and treating “high risk RA patients” using a therapeuticallyeffective amount of an IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof).

It is another object of the disclosure to provide methods of determiningthe likelihood that an RA patient will respond to treatment with anIL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof), by determining whether that patient is a high risk RA patient.

It is another object of the disclosure to provide methods of treating aninflammatory arthritis, e.g., AS, RA and PsA, using a therapeuticallyeffective amount of an IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof), by delivering such IL-7 antagonist aspart of a therapeutic regimen, e.g., during an induction regimen and amaintenance regimen.

Accordingly, disclosed herein are methods of treating rheumatoidarthritis (RA), comprising administering a therapeutically effectiveamount of an IL-17 antagonist to a high risk RA patient.

Disclosed herein are also methods of treating rheumatoid arthritis (RA),comprising: a) selecting a patient for treatment on the basis of thepatient being a high risk RA patient; and b) administering atherapeutically effective amount of an IL-17 antagonist to the patient.

Disclosed herein are methods of treating rheumatoid arthritis (RA),comprising: a) assaying a sample from a patient for: i. rheumatoidfactor (RF), anti-citrullinated protein antibody (ACPA), or RF and ACPA;and ii. C-reactive protein (CRP), an erythrocyte sedimentation rate(ESR), or both CRP and an ESR; and b) thereafter, administering thepatient an IL-17 antagonist to the patient if the patient is RF+, ACPA+,or RF+ and ACPA+ and the patient has a high level of CRP, a high ESR, ora high level of CRP and a high ESR.

Disclosed herein are methods of treating rheumatoid arthritis (RA),comprising administering a therapeutically effective amount of an IL-17antagonist to a patient, provided that the patient is selected fortreatment on the basis of: a) being RF+, ACPA+, or both RF+ and ACPA+;and b) having a high level of CRP, a high ESR, or both a high level ofCRP and a high ESR. In some embodiments, the step of administeringcomprises: a) administering the IL-17 antagonist to the patient duringan induction regimen; and b) thereafter administering the IL-17antagonist to the patient during a maintenance regimen.

Disclosed herein are methods of treating rheumatoid arthritis (RA),comprising: a) administering a high risk RA patient three doses of about10 mg/kg of an IL-17 antagonist, each of the three doses being deliveredevery other week; and b) thereafter administering about 75 mg-about 150mg of the IL-17 antagonist to the patient every month, beginning onemonth from delivery of the third intravenous dose.

Disclosed herein are therapeutic regimens for treating rheumatoidarthritis (RA), comprising: a) selecting a patient having RA based onthe following criteria; i. the patient is RF+, ACPA+, or both RF+ andACPA+; and ii. the patient has a high level of CRP, a high ESR, or botha high level of CRP and a high ESR; and b) administering the patientthree doses of about 10 mg/kg of an IL-17 antagonist, the first dosebeing delivered during week zero, the second dose being delivered duringweek two, and the third dose being delivered during week four; and c)thereafter administering the patient about 75 mg-about 150 mg of theIL-17 antagonist twice a month, monthly, every two months or every threemonths, beginning during week eight.

Disclosed herein are methods of determining the likelihood that an RApatient will respond to treatment with an IL-17 antagonist, comprisingassaying a sample from the patient for: a) rheumatoid factor (RF),anti-citrullinated protein antibody (ACPA), or RF and ACPA; and b)C-reactive protein (CRP), an erythrocyte sedimentation rate (ESR), orboth CRP and an ESR, wherein the patient is likely to respond totreatment of RA with the IL-17 antagonist if the patient is RF+, ACPA+,or RF+ and ACPA+; and the patient has a high level of CRP, a high ESR,or a high level of CRP and a high ESR.

Disclosed herein are IL-17 antagonists for use in treating rheumatoidarthritis (RA), characterized in that the IL-17 antagonist is to beadministered to a high risk RA patient. Disclosed herein are IL-17antagonists for use in treating rheumatoid arthritis (RA), characterizedin that the IL-17 antagonist is to be administered to a patient selectedfor treatment on the basis of the patient being a high risk RA patient.

Disclosed herein are IL-17 antagonists for use in treating a high riskRA patient. In some embodiments, the high risk RA patient: a) isseropositive for rheumatoid factor (RF+), anti-citrullinated proteinantibody (ACPA+), or both RF+ and ACPA+; and b) has a high level ofC-reactive protein (CRP), a high erythrocyte sedimentation rate (ESR),or both a high level of CRP and a high ESR. In some embodiments, a highlevel of CRP is ≥10 mg/L, as measured by hsCRP. In some embodiments, ahigh ESR is ≥28 mm/h.

Disclosed herein are IL-17 antagonists for use in treating rheumatoidarthritis (RA), characterized in that the IL-17 antagonist is to beadministered to a patient, provided that the patient is selected fortreatment on the basis of: a) being RF+, ACPA+, or both RF+ and ACPA+;and b) having a high level of CRP, a high ESR, or both a high level ofCRP and a high ESR.

Disclosed herein are IL-17 antagonists for use in treating rheumatoidarthritis (RA), characterized in that the IL-17 antagonist is to be: a)administered to a high risk RA patient as three doses of about 10 mg/kg,each of the three doses being delivered every other week; and b)thereafter administered to the patient as a dose of about 75 mg-about150 mg every month, beginning one month from delivery of the thirdintravenous dose.

Disclosed herein are IL-17 antagonists for use in treating rheumatoidarthritis (RA), characterized in that: a) a sample from a patient isassayed for: i. rheumatoid factor (RF), anti-citrullinated proteinantibody (ACPA), or RF and ACPA; and ii.C-reactive protein (CRP), anerythrocyte sedimentation rate (ESR), or both CRP and an ESR; and b) theIL-17 antagonist is administered to the patient if the patient is RF+,ACPA+, or RF+ and ACPA+ and the patient has a high level of CRP, a highESR, or a high level of CRP and a high ESR.

Disclosed herein are uses of an IL-17 antagonist for the manufacture ofa medicament for treating RA, characterized in that the IL-17 antagonistis to be administered to high risk RA patient.

Disclosed herein are uses of an IL-17 antagonist for the manufacture ofa medicament for treating RA, characterized in that the IL-17 antagonistis to be administered to high risk RA patient during an inductionregimen followed by a maintenance regimen.

Disclosed herein are pharmaceutical composition for treating RA,comprising as an active ingredient an IL-17 antagonist, wherein theIL-17 antagonist is to be administered to a high risk RA patient.

Disclosed herein are pharmaceutical composition for treating RA,comprising as an active ingredient an IL-17 antagonist, wherein theIL-17 antagonist is to be administered to a high risk RA patient duringan induction regimen followed by a maintenance regimen.

Disclosed herein are therapeutic regimens for treating RA, comprising:a) selecting a high risk RA patient; b) administering about 10 mg/kg ofan IL-17 antagonist to the patient during weeks 0, 2 and 4; and c)thereafter administering about 75 mg-about 150 mg of the IL-17antagonist to the patient monthly, beginning week 8.

Disclosed herein are methods of treating a RA patient or a high risk RApatient, comprising: a) administering an IL-17 binding molecule to apatient in need thereof during an induction regimen that provides a meanmaximum plasma concentration (C_(max)) of the IL-17 binding molecule ofabout 360 μg/ml; and b) thereafter administering the IL-17 bindingmolecule to the patient during a maintenance regimen that provides: i)an average steady-state trough level of the IL-17 binding moleculebetween about 8 μg/ml-about 30 μg/ml; and/or ii) a mean AUC tau atsteady state of about 331 mg*day/L-about 1323 mg*day/L.

Disclosed herein are IL-17 binding molecules for use in treating a RApatient or a high risk RA patient, characterized in that the IL-17binding molecule: a) is to be administered to the patient during aninduction regimen that provides a mean maximum plasma concentration(C_(max)) of the IL-17 binding molecule of about 360 μg/ml; and b)thereafter, is to be administered to the patient during a maintenanceregimen that provides: i) an average steady-state trough level of theIL-17 binding molecule between about 8 μg/ml-about 30 μg/ml; and/or ii)a mean AUC tau at steady state of about 331 mg*day/L-about 1323mg*day/L.

Disclosed herein are methods of treating a high risk RA patient,comprising: a) administering an IL-17 binding molecule to a patient inneed thereof during an induction regimen that provides a mean maximumplasma concentration (C_(max)) of the IL-17 binding molecule of about401 μg/ml; and b) thereafter administering the IL-17 binding molecule tothe patient during a maintenance regimen that provides: i) an averagesteady-state trough level of the IL-17 binding molecule of about 9.4μg/ml-about 31 μg/ml; and/or ii) a mean AUC tau at steady state of about314 mg*day/L-about 1256 mg*day/L.

Disclosed herein are IL-17 binding molecule for use in treatingpsoriasis, characterized in that the IL-17 binding molecule: a) is to beadministered to the patient during an induction regimen that provides amean maximum plasma concentration (C_(max)) of the IL-17 bindingmolecule of about 401 μg/ml; and b) thereafter, is to be administered tothe patient during a maintenance regimen that provides: i) an averagesteady-state trough level of the IL-17 binding molecule of about 9.4μg/ml-about 31 μg/ml; and/or ii) a mean AUC tau at steady state of about314 mg*day/L-about 1256 mg*day/L.

In some embodiments, the maintenance regimen provides an averagesteady-state trough level of the IL-17 binding molecule of about 9.4μg/ml-about 17.3 μg/ml. In some embodiments, the maintenance provides anaverage steady-state trough level of the IL-17 binding molecule of about9.4 μg/ml or about 17.3 μg/ml. In some embodiments, the inductionregimen comprises intravenous administration of the IL-17 bindingmolecule every other week. In some embodiments, the maintenance regimencomprises monthly subcutaneous administration of the IL-17 bindingmolecule.

Disclosed herein are kits comprising: a) a pharmaceutical compositioncomprising an IL-17 antagonist for use in the treatment of rheumatoidarthritis (RA) in a patient; and b) instructions describing how toadminister said pharmaceutical composition to the patient, wherein thepatient is characterized as: i) being RF+, ACPA+, or both RF+ and ACPA+;and ii) having a high level of CRP, a high ESR, or both a high level ofCRP and a high ESR.

Disclosed herein are IL-17 antagonists in preparation of a medicamentfor the treatment of RA, provided that the patient is selected for thetreatment on the basis of: a) being RF+, ACPA+, or both RF+ and ACPA+;and b) having a high level of CRP, a high ESR, or both a high level ofCRP and a high ESR.

Disclosed herein are IL-17 antagonists for the manufacture of amedicament for the treatment of RA in a patient characterized as: a)being RF+, ACPA+, or both RF+ and ACPA+; and b) having a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR, wherein themedicament is formulated to comprise containers, each container having asufficient amount of the IL-17 antagonist to allow delivery of at leastabout 75 mg-about 150 mg IL-17 antagonist per unit dose.

Disclosed herein are IL-17 antagonists for the manufacture of amedicament for the treatment of RA in a patient characterized as: a)being RF+, ACPA+, or both RF+ and ACPA+; and b) having a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR, wherein themedicament is formulated to comprise containers, each container having asufficient amount of the IL-17 antagonist to allow delivery of at leastabout 10 mg/kg per unit dose.

Disclosed herein are IL-17 antagonists for the manufacture of amedicament for the treatment of RA in a patient characterized as: a)being RF+, ACPA+, or both RF+ and ACPA+; and b) having a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR, wherein themedicament is formulated at a dosage to allow intravenous delivery ofabout 10 mg/kg per unit dose.

Disclosed herein are IL-17 antagonists for the manufacture of amedicament for the treatment of RA in a patient characterized as: a)being RF+, ACPA+, or both RF+ and ACPA+; and b) having a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR, wherein themedicament is formulated at a dosage to allow subcutaneous delivery ofabout 75 mg-about 150 mg IL-17 antagonist per unit dose.

Disclosed herein are in vitro test methods for selecting a patient fortreatment of RA, comprising determining if: i. the patient is RF+,ACPA+, or both RF+ and ACPA+; and ii. the patient has a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR. In someembodiments of the disclosed in vitro test methods, the patient has animproved therapeutic response to the following regimen: a) administeringthe patient three doses of about 10 mg/kg of an IL-17 antagonist, thefirst dose being delivered during week zero, the second dose beingdelivered during week two, and the third dose being delivered duringweek four; and a) thereafter administering the patient about 75 mg-about150 mg of the IL-17 antagonist twice a month, monthly, every two monthsor every three months, beginning during week eight.

Disclosed herein are methods for producing a transmittable form ofinformation on a patient having RA, comprising: a) assaying a samplefrom the patient for: i) rheumatoid factor (RF), anti-citrullinatedprotein antibody (ACPA), or RF and ACPA; and ii) C-reactive protein(CRP), an erythrocyte sedimentation rate (ESR), or both CRP and an ESR;and b) embodying the result of step a) in a transmittable form ofinformation.

Herein are also provided methods of treating an inflammatory arthritis,comprising administering three induction doses (e.g., i.v., inductiondoses) of about 10 mg/kg or several (e.g., 1, 2, 3, 4, or 5) inductiondoses of about 150 mg (e.g., s.c. induction doses) of an IL-17antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof) to a patient having an inflammatory arthritis selected from thegroup consisting of rheumatoid arthritis (RA), spondyloarthropathy,ankylosing spondylitis (spondylarthritis), and psoriatic arthritis. Insome embodiments, the induction doses are delivered every other week,and thereafter the patient is administered monthly maintenance doses(e.g., s.c. maintenance doses) of about 75 mg-about 300 mg (e.g., about75 mg-about 150 mg, e.g., about 75 mg or about 150 mg) of the IL-17antagonist (e.g., secukinumab), e.g., beginning one month from deliveryof the final induction dose.

Herein are also provided methods of treating RA, comprising selecting aRA patient (e.g., a high risk RA patient) or a patient having elevatedbaseline CRP levels, administering the patient about 10 mg/kg (e.g., byan i.v. route) of an IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof) every other week (e.g., during week 0,2 and 4), and thereafter administering the patient about 75 mg-about 300mg (e.g., about 75 mg-about 150 mg, e.g., about 75 mg or about 150 mg)(e.g., by an s.c. route) of the IL-17 antagonist on a monthly basis(e.g., beginning week 8).

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the high risk RA patient: a) is seropositivefor rheumatoid factor (RF+), anti-citrullinated protein antibody(ACPA+), or both RF+ and ACPA+; and b) has a high level of C-reactiveprotein (CRP), a high erythrocyte sedimentation rate (ESR), or both ahigh level of CRP and a high ESR.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the IL-17 antagonist is an IL-17 bindingmolecule or an IL-17 receptor binding molecule. In some embodiments, theIL-17 binding molecule or an IL-17 receptor binding molecule is an IL-17binding molecule (e.g., IL-17 antibody) selected from the groupconsisting of: a) secukinumab; b) an IL-17 antibody that binds to anepitope of IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Val124,Thr125, Pro126, Ile127, Val128, His129; c) an IL-17 antibody that bindsto an epitope of IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80; d)an IL-17 antibody that binds to an epitope of an IL-17 homodimer havingtwo mature IL-17 protein chains, said epitope comprising Leu74, Tyr85,His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 onone chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain; e)an IL-17 antibody that binds to an epitope of an IL-17 homodimer havingtwo mature IL-17 protein chains, said epitope comprising Leu74, Tyr85,His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 onone chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain,wherein the IL-17 binding molecule has a K_(D) of about 100-200 pM, andwherein the IL-17 binding molecule has an in vivo half-life of about 4weeks; and f) an IL-17 antibody that comprises an antibody selected fromthe group consisting of: i) an immunoglobulin heavy chain variabledomain (V_(H)) comprising the amino acid sequence set forth as SEQ IDNO:8; ii) an immunoglobulin light chain variable domain (V_(L))comprising the amino acid sequence set forth as SEQ ID NO:10; iii) animmunoglobulin V_(H) domain comprising the amino acid sequence set forthas SEQ ID NO:8 and an immunoglobulin V_(L) domain comprising the aminoacid sequence set forth as SEQ ID NO:10; iv) an immunoglobulin V_(H)domain comprising the hypervariable regions set forth as SEQ ID NO:1,SEQ ID NO:2, and SEQ ID NO:3; v) an immunoglobulin V_(L) domaincomprising the hypervariable regions set forth as SEQ ID NO:4, SEQ IDNO:5 and SEQ ID NO:6; vi) an immunoglobulin V_(H) domain comprising thehypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ IDNO:13; vii) an immunoglobulin V_(H) domain comprising the hypervariableregions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and animmunoglobulin V_(L) domain comprising the hypervariable regions setforth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; and viii) animmunoglobulin V_(H) domain comprising the hypervariable regions setforth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 and animmunoglobulin V_(L) domain comprising the hypervariable regions setforth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.

In preferred embodiments of the disclosed methods, kits, uses,pharmaceutical compositions, and regimens, the IL-17 binding molecule isa human antibody. In even more preferred embodiments of the disclosedmethods, kits, uses, pharmaceutical compositions, and regimens, theIL-17 binding molecule is secukinumab.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the study design of the CAIN457F2201 study.

FIG. 2A shows ACR20 response last observation carried forward (LOCF) bytreatment up to week 16 in study CAIN457F2201 in full analysis set(FAS).

FIG. 2B shows ACR20 response (LOCF) by treatment up to week 16 in highrisk RA patients.

FIG. 2C shows the ACR20 response over time through week 52 by responders(R) and non-responders (NR) in the FAS.

FIG. 3A shows ACR50 response (LOCF) by treatment up to week 16 in studyCAIN457F2201 in full analysis set (FAS).

FIG. 3B shows the ACR50 response over time through week 52 by responders(R) and non-responders (NR) in the FAS.

FIG. 4A shows ACR70 response (LOCF) by treatment up to week 16 in studyCAIN457F2201 in full analysis set (FAS).

FIG. 4B shows the ACR70 response over time through week 52 by responders(R) and non-responders (NR) in the FAS.

FIG. 5A shows DAS28-CRP change from baseline (LOCF) by treatment up toweek 16 in study CAIN457F2201 FAS.

FIG. 5B shows the DAS28-CRP response over time through week 52 byresponders (R) and non-responders (NR) in the FAS.

FIG. 6A shows HAQ© scores change from baseline (LOCF) by treatment up toweek 16 in study CAIN457F2201 FAS.

FIG. 6B shows the HAQ© response over time through week 52 by responders(R) and non-responders (NR) in the FAS.

FIG. 7 shows the ACR20/50/70 response at week 52 by responders (R) andnon-responders (NR) in the FAS.

FIG. 8A shows the ACR20/50/70% response at week 16 in the high risk RApatients and non-high risk RA patients.

FIG. 8B shows the DAS28-CRP response at week 16 in the high risk RApatients and non high risk RA patients.

FIG. 9 shows ACR20 responder rates by dose group and CRP baseline levelsin CAIN457F2201 study. Columns represent, from the left to the right,all patients, patients with a CRP baseline greater than 10 mg/L, greaterthan 20 mg/L, and greater than 30 mg/L, respectively.

FIG. 10 shows simulated secukinumab pharmacokinetics (PK) in rheumatoidarthritis patients. The full line shows PK without an induction strategy(one dose of 300 mg s.c. at Week 0), dotted line shows PK with asubcutaneous induction strategy (300 mg s.c. at Weeks 0, 1, 2, 3 and 4)and dashed line shows PK with an intravenous induction strategy (10mg/kg i.v. at Weeks 0, 2 and 4). Each of the three options is followedby 300 mg s.c. every 4 weeks for maintenance.

FIG. 11 provides a Bayesian analysis of the Week 6 ASAS20 response ratesof patients with moderate to severe AS treated with AIN457 i.v. given 3weeks apart (trial CAIN457A2209, Example 5).

DETAILED DESCRIPTION OF THE DISCLOSURE

The 1987 American College of Rheumatology (ACR) classification criteriafor RA discriminates patients with established RA from individuals witha combination of other definite rheumatological diagnoses. Thesecriteria were not helpful in identifying patients with early RA diseasewho might benefit from early intervention. In 2010 ACR provided a newclassification system that focuses on RA features at earlier stages ofdisease that are associated with persistent and/or erosive disease(hereinafter “2010 ACR/EULAR” criteria). Aletaha et al. (2010) Ann.Rheum. Dis. 69:1580-1588. The 2010 ACR/EULAR classification systemfocuses on six criteria; the first two criteria define who should betested for RA, while the remaining four criteria are scored (Table 1). Ascore of six or greater is indicative of definite RA.

TABLE 1 The 2010 American College of Rheumatology/European LeagueAgainst Rheumatism classification Criteria for Rheumatoid Arthritis (RA)Score Target population (Who should be tested?): Patients who 1) have atleast 1 joint with definite clinical synovitis (swelling)* 2) with thesynovitis not better explained by another disease† Classificationcriteria for RA (score-based algorithm: add score of categories A-D; ascore of ≥6/10 is needed for classification of a patient as havingdefinite RA)‡ A. Joint involvement§ 1 large joint¶ 0 2-10 large joints 11-3 small joints (with or without involvement of large 2 joints)# 4-10small joints (with or without involvement of large 3 joints) >10 joints(at least 1 small joint)** 5 B. Serology (at least 1 test result isneeded for classification)†† Negative RF and negative ACPA 0Low-positive RF or low-positive ACPA 2 High-positive RF or high-positiveACPA 3 C. Acute-phase reactants (at least 1 test result is needed forclassification)‡‡ Normal CRP and normal ESR 0 Abnormal CRP or abnormalESR 1 D. Duration of symptoms§§ <6 weeks 0 ≥6 weeks 1 *The criteria areaimed at classification of newly presenting patients. In addition,patients with erosive disease typical of rheumatoid arthritis (RA) witha history compatible with prior fulfillment of the 2010 criteria shouldbe classified as having RA. Patients with longstanding disease,including those whose disease is inactive (with or without treatment)who, based on retrospectively available data, have previously fulfilledthe 2010 criteria should be classified as having RA. †Differentialdiagnoses vary among patients with different presentations, but mayinclude conditions such as systemic lupus erythematosus, psoriaticarthritis, and gout. If it is unclear about the relevant differentialdiagnoses to consider, an expert rheumatologist should be consulted.‡Although patients with a score of <6/10 are not classifiable as havingRA, their status can be reassessed and the criteria might be fulfilledcumulatively over time. §Joint involvement refers to any swollen ortender joint on examination, which may be confirmed by imaging evidenceof synovitis. Distal interphalangeal joints, first carpometacarpaljoints, and first metatarsophalangeal joints are excluded fromassessment. Categories of joint distribution are classified according tothe location and number of involved joints, with placement into thehighest category possible based on the pattern of joint involvement.¶“Large joints” refers to shoulders, elbows, hips, knees, and ankles.#“Small joints” refers to the metacarpophalangeal joints, proximalinterphalangeal joints, second through fifth metatarsophalangeal joints,thumb interphalangeal joints, and wrists. **In this category, at least 1of the involved joints must be a small joint; the other joints caninclude any combination of large and additional small joints, as well asother joints not specifically listed elsewhere (e.g., temporomandibular,acromioclavicular, sternoclavicular, etc.). ††Negative refers to IUvalues that are less than or equal to the upper limit of normal (ULN)for the laboratory and assay; low-positive refers to IU values that arehigher than the ULN but </=3 times the ULN for the laboratory and assay;high-positive refers to IU values that are >3 times the ULN for thelaboratory and assay. Where rheumatoid factor (RF) information is onlyavailable as positive or negative, a positive result should be scored aslow-positive for RF. ACPA = anti-citrullinated protein antibody.‡‡Normal/abnormal is determined by local laboratory standards. CRP =C-reactive protein; ESR = erythrocyte sedimentation rate. §§Duration ofsymptoms refers to patient self-report of the duration of signs orsymptoms of synovitis (e.g., pain, swelling, tenderness) of joints thatare clinically involved at the time of assessment, regardless oftreatment status.

In searching for indicators predictive of an RA patient's response totreatment with an IL-17 binding molecule, e.g., an IL-17 antibody, suchas secukinumab, we have analyzed two of the four 2010 ACR/EULARscoreable criteria to determine whether these criteria influenceresponse to treatment with an IL-17 binding molecule, such assecukinumab. First, we analyzed patient serology to determine whetherthe patient is RF+ and/or ACPA+. Second, we analyzed the presence ofacute-phase reactants to determine whether the patient has a high levelof C-reactive protein (CRP) and/or a high erythrocyte sedimentation rate(ESR). In the process, we discovered that patients: 1) that are RF+ orACPA+(or both); and 2) who have a high level of CRP or ESR (or both) aremore likely to have a good response to treatment with an IL-17 bindingmolecule, e.g., an IL-17 antibody, such as secukinumab. Such patients(termed herein “high risk RA patients”) are those with the most salientfeatures of RA. (See, e.g., Yildirim et al. (2004) Annals Clin. Lab. Sci34:423). Accordingly, disclosed herein are methods of treatingrheumatoid arthritis (RA), comprising administering a therapeuticallyeffective amount of an IL-17 binding molecule to a high risk RA patient.

We have additionally determined that elevated baseline CRP levels(e.g., >about 10 mg/L) are also associated with responsiveness tosecukinumab. Accordingly, disclosed herein are methods of treatingrheumatoid arthritis (RA), comprising administering a therapeuticallyeffective amount of an IL-17 binding molecule to a RA patient displayingelevated baseline CRP levels (e.g., greater than about 10 mg/L, greaterthan about 20 mg/L, greater than about 30 mg/L).

We have further discovered that the treatment regimens useful intreating high risk RA patients are additionally useful in treating RA innon-high risk patients and patients having other inflammatory arthritis,e.g., ankylosing spondylitis (AS) or psoriatic arthritis (PsA).Accordingly, disclosed herein are dosing and treatment regimens foraddressing inflammatory arthridities (e.g., RA, AS, PsA), comprisingadministering a therapeutically effective amount of an IL-17 bindingmolecule to a patient having an inflammatory arthridities.

The term “comprising” encompasses “including” as well as “consisting,”e.g. a composition “comprising” X may consist exclusively of X or mayinclude something additional, e.g., X+Y.

The term “about” in relation to a numerical value x means+/−10% unlessthe cotext dictates otherwise. The term “about,” when used in referenceto a pharmacokinetic (PK) parameter (e.g., AUC, C_(max), t_(max), troughlevels, etc.), indicates a treatment (e.g., dosage and/or dosingregimen) that a skilled artisan would consider bioequivalent to areference treatment. For bioequivalence, the standard method to showbioequivalence is to prove statistically that the ratio of a given PKparameter (e.g., AUC, C_(max)) between two treatments (i.e., a referencetreatment and a test treatment) is between 0.8-1.25, which is shown bymeans of a 90% confidence interval (CI) around the ratio (the lowerlimit of this CI being above 0.8, and the upper limit of this CI beingbelow 1.25). Thus, e.g., if during a trial comparing the PK profiles ofa reference treatment and a test treatment, a reference C_(max) of 10μg/ml is obtained, then the test treatment will be considered “about 10μg/ml” if a skilled artisan would consider the test treatment to bebioequivalent. As used herein, pharmacokinetic terms, e.g., t_(max),t_(1/2), AUC, AUC_((0-tau)) (AUC to the end of a given dosing period,hereinafter “AUC tau”), C_(max), have their art-accepted meanings.

The term “administering” in relation to a compound, e.g., an IL-17binding molecule or an anti-rheumatic agent, is used to refer todelivery of that compound by any route.

The phrase “active rheumatoid arthritis” or “active RA” is used to meanRA with visible signs and symptoms (e.g., swelling, difficulty inflexion, etc.).

The term “assaying” is used to refer to the act of detecting,identifying, screening, or determining, which act may be performed byany conventional means. For example, a sample may be assayed for thepresence of a particular marker by using an ELISA assay, a Northernblot, imaging, etc. to detect whether that marker is present in thesample.

The word “substantially” does not exclude “completely,” e.g., acomposition which is “substantially free” from Y may be completely freefrom Y. Where necessary, the word “substantially” may be omitted fromthe definition of the disclosure.

As used herein, “mg/kg” refers to mg of drug per kg body weight of thepatient being administered the drug.

“IL-17 antagonist” as used herein refers to a molecule capable ofantagonizing (e.g., reducing, inhibiting, decreasing, blocking,delaying) IL-17 function, expression and/or signalling (e.g., byblocking the binding of IL-17 to the IL-17 receptor). Non-limitingexamples of IL-17 antagonists include IL-17 binding molecules and IL-17receptor binding molecules. In some embodiments of the disclosedmethods, regimens, kits, processes, uses and compositions, an IL-17antagonist is employed.

By “IL-17 binding molecule” is meant any molecule capable of binding tothe human IL-17 antigen either alone or as it is associated with othermolecules. The binding reaction may be shown by standard methods(qualitative assays) including, for example, a binding assay,competition assay or a bioassay for determining the inhibition of IL-17binding to its receptor or any kind of binding assays, with reference toa negative control test in which an antibody of unrelated specificitybut of the same isotype, e.g. an anti-CD25 antibody, is used.Non-limiting examples of IL-17 binding molecules include smallmolecules, IL-17 receptor decoys, and antibodies as produced by B-cellsor hybridomas and chimeric, CDR-grafted or human antibodies or anyfragment thereof, e.g., F(ab′)₂ and Fab fragments, as well as singlechain or single domain antibodies. Preferably the IL-17 binding moleculeantagonizes (e.g., reduces, inhibits, decreases, delays) IL-17 function,expression and/or signalling. In some embodiments of the disclosedmethods, regimens, kits, processes, uses and compositions, an IL-17binding molecule is employed.

By “IL-17 receptor binding molecule” is meant any molecule capable ofbinding to the human IL-17 receptor either alone or associated withother molecules. The binding reaction may be shown by standard methods(qualitative assays) including, for example, a binding assay,competition assay or a bioassay for determining the inhibition of IL-17receptor binding to IL-17 or any kind of binding assays, with referenceto a negative control test in which an antibody of unrelated specificitybut of the same isotype, e.g. an anti-CD25 antibody, is used.Non-limiting examples of IL-17 receptor binding molecules include smallmolecules, IL-17 decoys, and antibodies to the IL-17 receptor asproduced by B-cells or hybridomas and chimeric, CDR-grafted or humanantibodies or any fragment thereof, e.g., F(ab′)2 and Fab fragments, aswell as single chain or single domain antibodies. Preferably the IL-17receptor binding molecule antagonizes (e.g., reduces, inhibits,decreases, delays) IL-17 function, expression and/or signalling. In someembodiments of the disclosed methods, regimens, kits, processes, usesand compositions, an IL-17 receptor binding molecule is employed.

The term “antibody” as referred to herein includes whole antibodies andany antigen-binding portion or single chains thereof. A naturallyoccurring antibody is a glycoprotein comprising at least two heavy (H)chains and two light (L) chains inter-connected by disulfide bonds. Eachheavy chain is comprised of a heavy chain variable region (abbreviatedherein as V_(H)) and a heavy chain constant region. The heavy chainconstant region is comprised of three domains, CH1, CH2 and CH3. Eachlight chain is comprised of a light chain variable region (abbreviatedherein as VL) and a light chain constant region. The light chainconstant region is comprised of one domain, CL. The V_(H) and V_(L)regions can be further subdivided into regions of hypervariability,termed complementarity determining regions (CDR), interspersed withregions that are more conserved, termed framework regions (FR). EachV_(H) and V_(L) is composed of three CDRs and four FRs arranged fromamino-terminus to carboxy-terminus in the following order: FR1, CDR1,FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and lightchains contain a binding domain that interacts with an antigen. Theconstant regions of the antibodies may mediate the binding of theimmunoglobulin to host tissues or factors, including various cells ofthe immune system (e.g., effector cells) and the first component (C1q)of the classical complement system. In some embodiments of the disclosedmethods, regimens, kits, processes, uses and compositions, an antibodyto IL-17 or the IL-17 receptor is employed.

The term “antigen-binding portion” of an antibody as used herein, refersto fragments of an antibody that retain the ability to specifically bindto an antigen (e.g., IL-17). It has been shown that the antigen-bindingfunction of an antibody can be performed by fragments of a full-lengthantibody. Examples of binding fragments encompassed within the term“antigen-binding portion” of an antibody include a Fab fragment, amonovalent fragment consisting of the V_(L), V_(H), CL and CH1 domains;a F(ab)2 fragment, a bivalent fragment comprising two Fab fragmentslinked by a disulfide bridge at the hinge region; a Fd fragmentconsisting of the V_(H) and CH1 domains; a Fv fragment consisting of theV_(L) and V_(H) domains of a single arm of an antibody; a dAb fragment(Ward et al., 1989 Nature 341:544-546), which consists of a V_(H)domain; and an isolated complementarity determining region (CDR).Exemplary antigen binding sites include the CDRs of secukinumab as setforth in SEQ ID NOs:1-6 and 11-13 (Table 4), preferably the heavy chainCDR3. Furthermore, although the two domains of the Fv fragment, V_(L)and V_(H), are coded for by separate genes, they can be joined, usingrecombinant methods, by a synthetic linker that enables them to be madeas a single protein chain in which the V_(L) and V_(H) regions pair toform monovalent molecules (known as single chain Fv (scFv); see, e.g.,Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc.Natl. Acad. Sci. 85:5879-5883). Such single chain antibodies are alsointended to be encompassed within the term “antibody”. Single chainantibodies and antigen-binding portions are obtained using conventionaltechniques known to those of skill in the art. In some embodiments ofthe disclosed methods, regimens, kits, processes, uses and compositions,a single chain antibody or an antigen-binding portion of an antibodyagainst IL-17 (e.g., secukinumab) or the IL-17 receptor is employed.

The term “pharmaceutically acceptable” means a nontoxic material thatdoes not interfere with the effectiveness of the biological activity ofthe active ingredient(s).

An “isolated antibody”, as used herein, refers to an antibody that issubstantially free of other antibodies having different antigenicspecificities (e.g., an isolated antibody that specifically binds IL-17is substantially free of antibodies that specifically bind antigensother than IL-17). An isolated antibody may be substantially free ofother cellular material and/or chemicals. An isolated antibody that“specifically binds” IL-17 may, however, be cross-reactive with otherantigens, such as IL-17 molecules from other species. In someembodiments of the disclosed methods, regimens, kits, processes, usesand compositions, the IL-17 antagonist is an isolated antibody.

The terms “monoclonal antibody” or “monoclonal antibody composition” asused herein refer to a preparation of antibody molecules of singlemolecular composition. A monoclonal antibody composition displays asingle binding specificity and affinity for a particular epitope. Insome embodiments of the disclosed methods, regimens, kits, processes,uses and compositions, the IL-17 antagonist is a monoclonal antibody.

The term “human antibody”, as used herein, is intended to includeantibodies having variable regions in which both the framework and CDRregions are derived from sequences of human origin. Furthermore, if theantibody contains a constant region, the constant region also is derivedfrom such human sequences, e.g., human germline sequences, or mutatedversions of human germline sequences or antibody containing consensusframework sequences derived from human framework sequences analysis asdescribed in Knappik, et al. (2000. J Mol Biol 296, 57-86). A “humanantibody” need not be produced by a human, human tissue or human cell.The human antibodies of the disclosure may include amino acid residuesnot encoded by human sequences (e.g., mutations introduced by random orsite-specific mutagenesis in vitro or by somatic mutation in vivo).However, the term “human antibody”, as used herein, is not intended toinclude antibodies in which CDR sequences derived from the germline ofanother mammalian species, such as a mouse, have been grafted onto humanframework sequences. In some embodiments of the disclosed methods,regimens, kits, processes, uses and compositions, the IL-17 antagonistis a human antibody.

The term “IL-17” refers to IL-17A, formerly known as CTLA8, and includeswild-type IL-17A from various species (e.g., human, mouse, and monkey),polymorphic variants of IL-17A, and functional equivalents of IL-17A.Functional equivalents of IL-17A according to the present disclosurepreferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, oreven 99% overall sequence identity with a wild-type IL-17A (e.g., humanIL-17A), and substantially retain the ability to induce IL-6 productionby human dermal fibroblasts.

The term “K_(D)” is intended to refer to the dissociation constant,which is obtained from the ratio of K_(d) to K_(a) (i.e. K_(d)/K_(a))and is expressed as a molar concentration (M). K_(D) values forantibodies can be determined using methods well established in the art.A method for determining the K_(D) of an antibody is by using surfaceplasmon resonance, or using a biosensor system such as a Biacore®system. In some embodiments of the invention the IL-17 antagonist, e.g.,IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof) binds human IL-17with a K_(D) of about 100-250 pM.

As used herein, the term “affinity” refers to the strength ofinteraction between antibody and antigen at single antigenic sites.Within each antigenic site, the variable region of the antibody “arm”interacts through weak non-covalent forces with antigen at numeroussites; the more interactions, the stronger the affinity. Standard assaysto evaluate the binding affinity of the antibodies toward IL-17 ofvarious species are known in the art, including for example, ELISAs,western blots and RIAs. The binding kinetics (e.g., binding affinity) ofthe antibodies also can be assessed by standard assays known in the art,such as by Biacore analysis. Assays to evaluate the effects of theantibodies on functional properties of IL-17 (e.g., receptor binding,preventing or ameliorating osteolysis) are described in further detailin the Examples.

As used herein, the term “subject” and “patient” includes any human ornonhuman animal. The term “nonhuman animal” includes all vertebrates,e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs,cats, horses, cows chickens, amphibians, reptiles, etc.

An antibody that “inhibits” one or more of IL-17 functional properties(e.g., biochemical, immunochemical, cellular, physiological or otherbiological activities, or the like) as determined according tomethodologies known to the art and described herein, will be understoodto relate to a statistically significant decrease in the particularactivity relative to that seen in the absence of the antibody (or when acontrol antibody of irrelevant specificity is present). An antibody thatinhibits IL-17 activity affects a statistically significant decrease,e.g., by at least 10% of the measured parameter, by at least 50%, 80% or90%, and in certain embodiments an antibody of the disclosure mayinhibit greater than 95%, 98% or 99% of IL-17 functional activity.

The term “derivative”, unless otherwise indicated, is used to defineamino acid sequence variants, and covalent modifications of an IL-17antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof) according to the present disclosure, e.g., of a specifiedsequence. A “functional derivative” includes a molecule having aqualitative biological activity in common with the disclosed IL-17antagonista, e.g., IL-17 binding molecules (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecules (e.g., IL-17 antibody or antigen binding fragmentthereof). A functional derivative includes fragments and peptide analogsof an IL-17 antagonist as disclosed herein. Fragments comprise regionswithin the sequence of a polypeptide according to the presentdisclosure, e.g., of a specified sequence. Functional derivatives of theIL-17 antagonists disclosed herein preferably comprise V_(H) and/orV_(L) domains that have at least about 65%, 75%, 85%, 95%, 96%, 97%,98%, or even 99% overall sequence identity with the V_(H) and/or V_(L)sequences of the IL-17 binding molecules disclosed herein (e.g., theV_(H) and/or V_(L) sequences of Table 4), or comprise CDRs that have atleast about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overallsequence identity with the CDRs of the IL-17 antagonists (e.g.,secukinumab) disclosed herein (e.g., have 1, 2, or 3 amino aciddifferences from the CDRs set forth in Table 4), and substantiallyretain the ability to bind the human IL-17 or, e.g., inhibit IL-6production of IL-17 induced human dermal fibroblasts.

“Inhibit IL-16” as used herein refers to the ability of an IL-17antagonist (e.g., secukinumab) to decrease IL-6 production from primaryhuman dermal fibroblasts. The production of IL-6 in primary human(dermal) fibroblasts is dependent on IL-17 (Hwang S Y et al., (2004)Arthritis Res Ther; 6:R120-128. In short, human dermal fibroblasts arestimulated with recombinant IL-17 in the presence of variousconcentrations of an IL-17 binding molecule or human IL-17 receptor withFc part. The chimeric anti-CD25 antibody Simulect® (basiliximab) may beconveniently used as a negative control. Supernatant is taken after 16 hstimulation and assayed for IL-6 by ELISA. An IL-17 antagonist, e.g.,IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof) as disclosed hereintypically has an IC₅₀ for inhibition of IL-6 production (in the presence1 nM human IL-17) of about 50 nM or less (e.g., from about 0.01 to about50 nM) when tested as above, i.e., said inhibitory activity beingmeasured on IL-6 production induced by hu-IL-17 in human dermalfibroblasts. In some embodiments of the disclosed methods, regimens,kits, processes, uses and compositions, IL-17 antagonists, e.g., IL-17binding molecules (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g.,IL-17 antibody or antigen binding fragment thereof) and functionalderivatives thereof have an IC₅₀ for inhibition of IL-6 production asdefined above of about 20 nM or less, more preferably of about 10 nM orless, more preferably of about 5 nM or less, more preferably of about 2nM or less, more preferably of about 1 nM or less.

The term “covalent modification” includes modifications of a polypeptideaccording to the present disclosure, e.g., of a specified sequence; or afragment thereof with an organic proteinaceous or non-proteinaceousderivatizing agent, fusions to heterologous polypeptide sequences, andpost-translational modifications. Covalent modified polypeptides, e.g.,of a specified sequence, still have the ability to bind the human IL-17or, e.g., inhibit IL-6 production of IL-17 induced human dermalfibroblasts by crosslinking. Covalent modifications are traditionallyintroduced by reacting targeted amino acid residues with an organicderivatizing agent that is capable of reacting with selected sides orterminal residues, or by harnessing mechanisms of post-translationalmodifications that function in selected recombinant host cells. Certainpost-translational modifications are the result of the action ofrecombinant host cells on the expressed polypeptide. Glutaminyl andasparaginyl residues are frequently post-translationally deamidated tothe corresponding glutamyl and aspartyl residues. Alternatively, theseresidues are deaminated under mildly acidic conditions. Otherpost-translational modifications include hydroxylation of proline andlysine, phosphorylation of hydroxyl groups of seryl, tyrosine orthreonyl residues, methylation of the α-amino groups of lysine,arginine, and histidine side chains, see, e.g., T. E. Creighton,Proteins: Structure and Molecular Properties, W. H. Freeman & Co., SanFrancisco, pp. 79-86 (1983). Covalent modifications, e.g., includefusion proteins comprising a polypeptide according to the presentdisclosure, e.g., of a specified sequence and their amino acid sequencevariants, such as immunoadhesins, and N-terminal fusions to heterologoussignal sequences.

The phrase “substantially identical” means that the relevant amino acidor nucleotide sequence (e.g., CDR(s), V_(H), or V_(L) domain) will beidentical to or have insubstantial differences (e.g., through conservedamino acid substitutions) in comparison to a particular referencesequence. Insubstantial differences include minor amino acid changes,such as 1 or 2 substitutions in a 5 amino acid sequence of a specifiedregion. In the case of antibodies, the substituted antibody has the samespecificity and has at least 50% of the affinity of the same. Sequencessubstantially identical (e.g., at least about 85% sequence identity) tothe sequences disclosed herein are also part of this application. Insome embodiments, the sequence identity can be about 90% or greater,e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher.

“Identity” with respect to a native polypeptide and its functionalderivative is defined herein as the percentage of amino acid residues inthe candidate sequence that are identical with the residues of acorresponding native polypeptide, after aligning the sequences andintroducing gaps, if necessary, to achieve the maximum percent identity,and not considering any conservative substitutions as part of thesequence identity. Neither N- or C-terminal extensions nor insertionsshall be construed as reducing identity. Methods and computer programsfor the alignment are well known. The percent identity can be determinedby standard alignment algorithms, for example, the Basic Local AlignmentSearch Tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol.,215: 403 410); the algorithm of Needleman et al. ((1970) J. Mol. Biol.,48: 444 453); or the algorithm of Meyers et al. ((1988) Comput. Appl.Biosci., 4: 11 17). A set of parameters may be the Blosum 62 scoringmatrix with a gap penalty of 12, a gap extend penalty of 4, and aframeshift gap penalty of 5. The percent identity between two amino acidor nucleotide sequences can also be determined using the algorithm of E.Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has beenincorporated into the ALIGN program (version 2.0), using a PAM120 weightresidue table, a gap length penalty of 12 and a gap penalty of 4.

“Amino acid(s)” refer to all naturally occurring L-α-amino acids, e.g.,and include D-amino acids. The amino acids are identified by either thewell known single-letter or three-letter designations.

The term “amino acid sequence variant” refers to molecules with somedifferences in their amino acid sequences as compared to the sequencesaccording to the present disclosure. Amino acid sequence variants of apolypeptide according to the present disclosure, e.g., of a specifiedsequence, still have the ability to bind the human IL-17 or, e.g.,inhibit IL-6 production of IL-17 induced human dermal fibroblasts.Substitutional variants are those that have at least one amino acidresidue removed and a different amino acid inserted in its place at thesame position in a polypeptide according to the present disclosure,e.g., of a specified sequence. These substitutions may be single, whereonly one amino acid in the molecule has been substituted, or they may bemultiple, where two or more amino acids have been substituted in thesame molecule. Insertional variants are those with one or more aminoacids inserted immediately adjacent to an amino acid at a particularposition in a polypeptide according to the present disclosure, e.g., ofa specified sequence. Immediately adjacent to an amino acid meansconnected to either the α-carboxy or α-amino functional group of theamino acid. Deletional variants are those with one or more amino acidsin a polypeptide according to the present disclosure, e.g., of aspecified sequence, removed. Ordinarily, deletional variants will haveone or two amino acids deleted in a particular region of the molecule.

As used herein, a “therapeutically effective amount” refers to an amountof an IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17antibody or antigen binding fragment thereof, e.g., secukinumab) orIL-17 receptor binding molecule (e.g., IL-17 antibody or antigen bindingfragment thereof) that is effective, upon single or multiple doseadministration to a subject (such as a human patient) at treating,preventing, preventing the onset of, curing, delaying, reducing theseverity of, ameliorating at least one symptom of a disorder orrecurring disorder, or prolonging the survival of the subject beyondthat expected in the absence of such treatment. When applied to anindividual active ingredient (e.g., an IL-17 antagonist, e.g., IL-17binding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof)) administered alone,the term refers to that ingredient alone. When applied to a combination,the term refers to combined amounts of the active ingredients thatresult in the therapeutic effect, whether administered in combination,serially or simultaneously.

The terms “treatment” or “treat” refer to both prophylactic orpreventative treatment as well as curative or disease modifyingtreatment, including treatment of patient at risk of contracting thedisease or suspected to have contracted the disease as well as patientswho are ill or have been diagnosed as suffering from a disease ormedical condition, and includes suppression of clinical relapse. Thetreatment may be administered to a subject having a medical disorder orwho ultimately may acquire the disorder, in order to prevent, cure,delay the onset of, reduce the severity of, or ameliorate one or moresymptoms of a disorder or recurring disorder, or in order to prolong thesurvival of a subject beyond that expected in the absence of suchtreatment.

As used herein, the phrase “inflammatory arthritis” refers to a varietyof conditions of the joints that involve the immune system andinflammation, and includes autoimmune disorders, e.g., rhuematoidarthritis. Non-limiting examples include seronegativespondyloarthropathies such as AS, Reiter's syndrome, PsA, enteropathicarthritis, and other arthropathies such as RA, juvenile rheumatoidarthritis and systemic onset rheumatoid arthritis, crystaline arthritis(gout pseudogout, apatite gout), polymyalgia rheumatica, amyloidarthritis, pigment villonodular synovitis, synovial chondromatosis,hemophilic arthritis, and reactive synovitis. In some embodiments of thedisclosed methods, regimens, uses, kits, and pharmaceuticalcompositions, the patient has an inflammatory arthridities.

As used herein, the phrases “ankylosing spondylitis”, “AS’, and“spodyloarthropathy” refer to inflammatory arthridities characterized bychronic inflammation of joints, which can include the spine and thesacroilium in the pelvis, and which can cause eventual fusion of thespine. The modified New York criteria for AS or the ASAS axial SPAcriteria (2009) may be used to diagnose a patient as having AS. In someembodiments of the disclosed methods, regimens, uses, kits, andpharmaceutical compositions, the patient has AS.

As used herein, the phrase “psoriatic arthritis” and “PsA” refer to aninflammatory arthridities that is often associated with psoriasis of theskin. A variety of criteria, e.g. Moll and Wright criteria, ModifiedESSG criteria, McGonagle criteria, the Classification Criteria forPsoriatic Arthritis (CASPAR) criteria, etc. may be used to diagnose apatient as having PsA. In some embodiments of the disclosed methods,regimens, uses, kits, and pharmaceutical compositions, the patient hasPsA.

As used herein, “rheumatoid arthritis” or “RA” refers to a chronic,systemic inflammatory arthridities that may affect many tissues andorgans, but principally attacks synovial joints. The 2010 ACR/EULARcriteria may be used to diagnose a patient as having RA. In someembodiments of the disclosed methods, regimens, uses, kits, andpharmaceutical compositions, the patient has RA.

As used herein, the phrase “2010 ACR/EULAR criteria” refers to the 2010American College of Rheumatology/European League Against Rheumatismclassification criteria for RA found in Aletaha et al. (2010) Ann.Rheum. Dis. 69:1580-1588. That criteria, which is used to classify apatient as having rheumatoid arthritis, is set forth in Table 1.

As used herein, “C-reactive protein” and “CRP” refers to serumC-reactive protein, a plasma protein commonly used as an indicator ofthe acute phase response to inflammation. The level of CRP in plasma maybe given in any concentration, e.g., mg/dl, nmol/L. Levels of CRP may bemeasured by a variety of well known methods, e.g., radialimmunodiffusion, electroimmunoassay, immunoturbidimetry, ELISA,turbidimetric methods, fluorescence polarization immunoassay, and lasernephelometry. Testing for CRP may employ a standard CRP test or a highsensitivity CRP (hs-CRP) test (i.e., a high sensitivity test that iscapable of measuring low levels of CRP in a sample using lasernephelometry). Kits for detecting levels of CRP may be purchased fromvarious companies, e.g., Calbiotech, Inc, Cayman Chemical, RocheDiagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation,Aniara Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics, etc.

As used herein “high level of CRP” refers to an above normal CRP levelas defined in the 2010 ACR/EULAR criteria (Aletaha et al. (2010) Ann.Rheum. Dis. 69:1580-88). According to the 2010 ACR/EULAR criteria,normal/abnormal CRP is based on local laboratory standards. Each locallaboratory will employ a cutoff value for abnormal (high) CRP based onthat laboratory's rule for calculating normal maximum CRP. A physiciangenerally orders a CRP test from a local laboratory, and the locallaboratory reports normal or abnormal (low or high) CRP using the rulethat particular laboratory employs to calculate normal CRP. Thus, unlessthe context dictates otherwise, as used herein “high level of CRP” isnot meant to denote a particular numerical value, as what is considereda normal CRP value will differ between laboratories and assays. In someembodiments of the disclosure, a “high level of CRP” is >about 10 mg/L(e.g., 10 mg/L), >about 20 mg/L (e.g., 20 mg/L) or >about 30 mg/L (e.g.,30 mg/L). The CRP level, when assessed at baseline, is referred to as“baseline CRP”. A high level of CRP at baseline may be referred to as“elevated baseline CRP” or “high baseline CRP”. In some embodiments ofthe disclosed methods, regimens, uses, kits, and pharmaceuticalcompositions, the patient has a high baseline CRP (or hsCRP) or a highlevel of CRP (or hsCRP). The term “hsCRP” refers to the level of CRP inthe blood as measured by high sensitivity CRP testing.

As used herein, “erythrocyte sedimentation rate”, “ESR”, “sedimentationrate”, and “sedrate” refer to the rate of sedimentation of erythrocytesin a patient sample (e.g., plasma sample). An ESR reflects plasmaviscosity and the presence of acute phase proteins, and is normallyreported in “mm/hr”. ESR is performed by measuring the distance that redblood cells precipitate in a tube over time. Typical ESR testing methodsutilize the Westergren test, the Zeta Sedimentation Rate (ZSR) test andthe Wintrobe test. (See, Moseley and Bull (1982) Clin. Lab Haematol.4:169-78; Miller et al. (1983) Br Med J (Clin Res Ed) 286 (6361):266,Wetteland P et al. (1996) J. Intern. Med. 240 (3): 125-310, all of whichare incorporated by reference herein in their entirety). Commercial kitsfor measuring ESR are available from, e.g., ARKRAY USA, BD DiagnosticSystems, and Polymedco Inc. ESR instruments may be found, e.g, in U.S.Pat. No. 6,974,701, and from various companies, such as SteellexScientific, Nicesound Electronics Co., Globe Scientific Inc., Alifax,Analysis Instrument AB, Streck Laboratories, PolyMed Co, Inc., andQuantimetrix.

As used herein “high ESR” refers to an above normal ESR as defined inthe 2010 ACR/EULAR criteria (Aletaha et al. (2010) Ann. Rheum. Dis.69:1580-88). According to the 2010 ACR/EULAR criteria, normal/abnormalESR is based on local laboratory standards. Each local laboratory willemploy a cutoff value for abnormal (high) ESR based on that laboratory'srule for calculating normal maximum ESR. A physician generally orders anESR test from a local laboratory, and the local laboratory will reportnormal or high ESR using the rule that laboratory employs to calculatenormal ESR. Thus, unless the context dictates otherwise, as used herein“high ESR” is not meant to denote a particular numerical value, as whatis considered a normal ESR value will differ between laboratories andassays. In some embodiments of the disclosed methods, regimens, uses,kits, and pharmaceutical compositions, the patient has a high ESR.

As used herein, “rheumatoid factor” or “RF” refers to autoantibodiesagainst the Fc portion of IgG antibodies, which are often present in RApatients. As used herein “RF” includes any RF isotype, e.g., IgG, IgE,IgM and IgA. RF can be assayed using a variety of well-known techniquesthat are available to determine the presence or absence of a particularantibody, e.g., an ELISA assay, an agglutination test, a nephelometrytest, etc. RF levels may be reported by laboratories in a variety ofways, e.g., IU/ml, units/ml, and titer (using a dilution test to measurehow much a blood sample from a patient may be diluted before RF can nolonger be detected, e.g., a titer of 1:80 indicates more detectable RFthan a titer of 1:20). RF kits are commercially available, e.g., fromIBL—America (Immuno-Biological Laboratories).

A patient that is seropositive for RF is referred to herein as “RF+”.Similarly, if a sample from a patient has RF, then that sample is “RF+”.Each local laboratory will employ a cutoff value for normal RF levelsbased on that laboratory's rule for calculating normal maximum RF. Assuggested by Aletaha et al. (2010) Ann. Rheum. Dis. 69:1580-1588, apatient will be considered RF+ based on the upper limit of normal [ULN]for the respective laboratory test and assay; a patient is RF+ if avalue greater than the ULN for the respective laboratory test and assayis determined. Accordingly, unless the context dictates otherwise, asused herein “RF+” is not meant to denote a particular numerical value,as the ULN will differ between laboratories and assays. As anon-limiting example, at the time of testing, Laboratory X gives thenormal range of RF in the blood as 14-60 units/mL. At the time oftesting, Laboratory Y gives the normal range of RF in the blood as ≤40IU/ml. At the time of testing, Laboratory Z gives the normal range of RFin the blood as 1:20 to 1:80 titer. Thus, a patient would be RF+ ifLaboratory X returned an RF level of greater than 60 units/ml, ifLaboratory Y returned an RF value of greater than 40 IU/ml, or ifLaboratory Z returned an RF titer greater than 1:80. In some embodimentsof the disclosed methods, regimens, uses, kits, and pharmaceuticalcompositions, the patient is RF+.

The term “seropositive” used to mean the presence of a specificsubstance (e.g., RF) in a patient's blood serum.

As used herein, “anti-citrullinated protein antibody”, “ACPA”,“anti-cyclic citrullinated peptide antibody” and “anti-CCP” refers toautoantibodies that bind citrullinated amino acid residues on proteins,which are found in the joints of in RA patients. Cyclic citrullinatedpeptides are used in in vitro tests (e.g., ELISA assays) to determinethe presence of ACPA in a patient's blood; as a result, an ACPA is alsoreferred to as an “anti-CCP” antibody. ACPA levels can be assayed usinga variety of well-known techniques that are available to determine thepresence or absence of a particular antibody, e.g., agglutination, ELISAassay, etc. ACPA kits are commercially available, e.g., the DIASTAT®anti-CCP test from Axis-Shield Diagnostics, Ltd. (UK) and AxSYMAnti-CCP® kit from Abbot Diagnostics (Germany).

A patient that is seropositive for ACPA is referred to herein as“ACPA+”. Similarly, if a sample from a patient has ACPA, then thatsample is “ACPA+”. Each local laboratory will employ a cutoff value fornormal ACPA levels based on that laboratory's rule for calculatingnormal maximum ACPA. As suggested by Aletaha et al. (2010) Ann. Rheum.Dis. 69:1580-1588, a patient will be considered ACPA+ based on the upperlimit of normal [ULN] for the respective laboratory test and assay; apatient is ACPA+ if a value greater than the ULN for the respectivelaboratory test and assay is determined. Accordingly, unless the contextdictates otherwise, as used herein “ACPA+” is not meant to denote aparticular numerical value, as the ULN will differ between laboratoriesand assays. As a non-limiting, at the time of testing, Laboratory Agives the reference range of ACPA in the blood as <20 EU (arbitraryELISA units). At the time of testing, Laboratory B gives the referencerange of ACPA in the blood as <5 U/ml. Thus, a patient would be ACPA+ ifLaboratory A returned an ACPA value greater than 20 EU or if LaboratoryB returned an ACPA value of greater than 5 U/ml. In some embodiments ofthe disclosed methods, regimens, uses, kits, and pharmaceuticalcompositions, the patient is ACPA+.

Select normal/abnormal and reference ranges for ACPA, ESR, RF and CRPmay be found, e.g., in Fischbach and Dunning (2009) “A Manual ofLaboratory and Diagnostic Tests” (8^(th) Edition) WoltersKluwer/Lippincott Williams and Williams, which is incorporated byreference herein in its entirety.

As used herein, the phrase “high risk RA patient” is used to define apatient that: a) is RF+, ACPA+ or both RF+ and ACPA+; and b) has a highlevel of CRP (or hsCRP), a high ESR, or both a high level of CRP and ahigh ESR. In some embodiments of the disclosed methods, regimens, uses,kits, and pharmaceutical compositions, the patient is a high risk RApatient. In some embodiments, the patient presents with involvement ofat least one, two, three four, five, six, seven, eight, nine or tensmall joints. In some embodiments, the patient presents with involvementof at least one, two, three four, five, six, seven, eight, nine or tenlarge joints. In some embodiments, the patient presents with involvementof greater than ten joints, with at least one of the joints being asmall joint. In some embodiments, the patient has duration of symptomsof at least six weeks.

“Joint involvement” refers to any swollen or tender joint onexamination, which may be confirmed by imaging evidence of synovitis.Categories of joint distribution are classified according to thelocation and number of involved joints, with placement into the highestcategory possible based on the pattern of joint involvement. “Largejoints” refers to shoulders, elbows, hips, knees, and ankles. “Smalljoints” refers to the metacarpophalangeal joints, proximalinterphalangeal joints, second through fifth metatarsophalangeal joints,thumb interphalangeal joints, and wrists. In some embodiments of thedisclosed methods, regimens, uses, kits and compositions, a patient hasz 6 out of 28 tender joints and z 6 out of 28 swollen joints andhsCRP>10 mg/L.

“Duration of symptoms” refers to patient self-report of the duration ofsigns or symptoms of synovitis (e.g., pain, swelling, tenderness) ofjoints that are clinically involved at the time of assessment,regardless of treatment status.

As used herein, “selecting a high risk RA patient for treatment” and“selecting a patient for treatment on the basis of the patient being ahigh risk RA patient” and “selected for treatment” is used to mean thata particular RA patient is chosen from a larger group or RA patientsbased on that particular patient fulfilling the high risk RA criteria(i.e., the patient is RF+, ACPA+, or both RF+ and ACPA+; and the patienthas a high level of CRP, a high ESR, or both a high level of CRP and ahigh ESR).

As used herein, the phrase “has been previously treated for RA” is usedto mean a patient that has previously undergone RA treatment using ananti-rheumatic agent, e.g., the patient is a failure, an inadequateresponder, or intolerant to a previous RA therapy, anti-rheumatic agentor treatment regimen. Such patients include those previously treatedwith MTX, DMARDs, and/or biologics, such as TNF alpha antagonists, etc.In some embodiments of the disclosed methods, regimens, uses, kits, andpharmaceutical compositions, the patient has been previously treated forRA.

As used herein, the phrase “has not been previously treated for RA” isused to mean a patient that has not previously undergone RA treatmentusing an anti-rheumatic agen, i.e., the patient is “naïve”. In someembodiments of the disclosed methods, regimens, uses, kits, andpharmaceutical compositions, the patient has not been previously treatedfor RA.

As used herein, a “failure” to a previous RA therapy refers to: (1) apatient who has no meaningful clinical benefit (primary lack ofefficacy); (2) a patient who has a measurable and meaningful response,but for whom response could be better, e.g., low RA disease activity orRA remission was not achieved (also termed “inadequate response”); (3) apatient who, after an initial good response, worsens (secondary loss ofefficacy); and (4) a patient who has a good response but discontinuesbecause of a side effect (also termed “intolerance”). Patients who showTNF inadequate response (TNF-IR) or intolerance to TNF would beconsidered TNF failures. Patients who show methotrexate inadequateresponse (MTX-IR) or intolerance to MTX would be considered MTXfailures. Patients who show DMARD inadequate response (DMARD-IR) orintolerance to DMARDs would be considered DMARD failures. In someembodiments of the disclosed methods, regimens, uses, kits, andpharmaceutical compositions, the patient is a TNF failure, a MTXfailure, or a DMARD failure.

By “therapeutic regimen” is meant the pattern of treatment of anillness, e.g., the pattern of dosing used during the treatment of RA. Atherapeutic regimen may include an induction regimen and a maintenanceregimen. Examples of therapeutic regimens for treatment of RA are givenin Table 2, none of which provide for treatment of a high risk RApatient.

TABLE 2 Examples of therapeutic regimens for biological treatment ofrheumatoid arthritis (RA) Induction Standard Route Regimen MaintenanceRegimen ADALIMUMAB s.c. NA 40 mg every other week. Humira ® Somepatients with RA not receiving methotrexate may benefit from increasingthe frequency to 40 mg every week. ETANERCEPT s.c. NA 50 mg once weeklywith Enbrel ® or without methotrexate (MTX). INFLIXIMAB i.v. 3 mg/kg at3 mg/kg every 8 weeks Remicade ® 0, 2, and 6 thereafter. For patientsweeks who have an incomplete response, consideration may be given toadjusting the dose up to 10 mg/kg or treating as often as every 4 weeks.CERTOLIZUMAB s.c. 400 mg (given 200 mg every other week; PEGOL Cimzia ®as two s.c. for maintenance dosing, doses of 200 400 mg every 4 weekscan mg) initially be considered. and at weeks 2 and 4. GOLIMUMAB s.c. NA50 mg administered once Simponi ® a month. ANAKINRA s.c. NA 100 mg/dayadministered Kineret  ® daily. RITUXIMAB i.v. two 1000 mg Subsequentcourses should Rituxan ® IV infusions be administered every 24 separatedby weeks or based on clinical 2 weeks (one evaluation, but not soonercourse). than every 16 weeks. ABATACEPT i.v. <60 kg = 500 Every 4 weeksthereafter. Orencia ® mg; 60 to 100 kg = 750 mg; >100 kg = 1000 mginitially, then 2 and 4 weeks after initial infuion TOCILIZUMAB i.v. NA4 mg/kg once every 4 Actemra ® weeks followed by an increase to 8 mg/kgbased on clinical response.

The phrase “induction regimen” or “induction period” refers to atreatment regimen (or the portion of a treatment regimen) that is usedfor the initial treatment of a disease. In some embodiments, thedisclosed methods, uses, kits, processes and regimens (e.g., methods oftreating an inflammatory arthridities, e.g., RA, such as a high risk RApatient) employ an induction regimen. The general goal of an inductionregimen is to provide a high level of drug to a patient during theinitial period of a treatment regimen. An induction regimen may employ(in part or in whole) administration of a greater dose of the drug thana physician would employ during a maintenance regimen, administering adrug more frequently than a physician would administer the drug during amaintenance regimen, or both. In some embodiments of the disclosedmethods, uses, kits, processes and regimens the induction dose may bedelivered during an induction regimen as a single high dose infusion(e.g., about 30 mg/kg). Alternatively, an induction dose may bedelivered as several (e.g., two or three) infusions (e.g., about 10mg/kg). Alternatively, an induction dose may be delivered as several(e.g., 1, 2, 3, 4, 5, 6 or more) subcutaneous injections (e.g., about75-300 mg). Delivery of drug during an induction regimen may be via asubcutaneous (s.c.) route, e.g., delivery of dosages of about 75mg-about 300 mg s.c. (e.g., about 75 mg s.c., about 150 mg s.c., about300 mg s.c.), or via an intravenous (i.v.) route, e.g., delivery ofdosages of about 1 mg/kg-about 30 mg/kg i.v. (e.g., about 1 mg/kg, about3 mg/kg, about 10 mg/kg, about 30 mg/kg) or any other route ofadministration (e.g, intramuscular, i.m.). In some embodiments of thedisclosed methods, compositions, kits, uses and regimens the IL-17antagonist (e.g., secukinumab) is delivered by i.v. administrationduring at least a portion of the induction regimen. In some embodiments,the induction regimen comprises administering a dose of about 1mg/kg-about 30 mg/kg, about 1 mg/kg-about 10 mg/kg, preferably about 10mg/kg of the IL-17 antagonist (e.g., secukinumab). In furtherembodiments, the induction doses are delivered weekly, bi-weekly, everyother week, or monthly, preferably every other week. In furtherembodiments, the induction regimen employs 1-10 doses of the IL-17antagonist (e.g., secukinumab), preferably three doses of the IL-17antagonist (e.g., secukinumab).

An induction regimen for delivery of an IL-17 antagonist, e.g., an IL-17binding molecule (e.g., an IL-17 antibody, such as secukinumab) or anIL-17 receptor binding molecule (e.g., an IL-17 receptor antibody) mayalso be designed using PK information (see Table 10), rather thanspecific dosages. For the disclosed uses, regimens and methods (e.g.,methods of treating an inflammatory arthridities, e.g., RA, such as ahigh risk RA patient), an artisan may deliver an IL-17 antagonist, e.g.,an IL-17 binding molecule (e.g., an IL-17 antibody, such as secukinumab)or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody)during an induction regimen to provide an average C_(max) of about 360μg/mL-about 401 μg/mL. Alternatively, an artisan may deliver an IL-17antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody,such as secukinumab) or an IL-17 receptor binding molecule (e.g., anIL-17 receptor antibody) during an induction regimen to provide anaverage C_(max) of about 401 μg/mL, with up to about a 30%-40% [+ or −]inter-patient variation for an average 90 kg human. Alternatively, anartisan may deliver an IL-17 antagonist, e.g., an IL-17 binding molecule(e.g., an IL-17 antibody, such as secukinumab) or an IL-17 receptorbinding molecule (e.g., an IL-17 receptor antibody) during an inductionregimen to provide an average C_(max) of about 360 μg/mL for an average75 kg human. Alternatively, an artisan may deliver an IL-17 antagonist,e.g., an IL-17 binding molecule (e.g., an IL-17 antibody, such assecukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17receptor antibody) during an induction regimen to provide trough levelsover 80 μg/mL over a 10 week period for an average 75 kg human. In someembodiments, the IL-17 antagonist is delivered week 0, 2 and 4 i.v.during an induction regimen to provide an average average C_(max) ofabout 401 μg/mL, with up to about a 30%-40% [+ or −] inter-patientvariation for an average 90 kg human. In some embodiments, the IL-17antagonist is delivered week 0, 2 and 4 i.v. during an induction regimento provide an average C_(max) of about 360 μg/mL for an average 75 kghuman. In other embodiments, the IL-17 antagonist is delivered week 0, 2and 4 i.v. during an induction regimen to provide trough levels over 80μg/mL over a 10 week period for an average 75 kg human.

The phrase “maintenance regimen” or “maintenance period” refers to atreatment regimen (or the portion of a treatment regimen) that is usedfor the maintenance of a patient during treatment of an illness, e.g.,to keep the patient in remission for long periods of time (months oryears). In some embodiments, the disclosed methods, uses and regimens(e.g., methods of treating an inflammatory arthridities, e.g., RA, suchas a high risk RA patient) employ a maintenance regimen. A maintenanceregimen may employ continuous therapy (e.g., administering a drug at aregular intervals, e.g., weekly, monthly, yearly, etc.) or intermittenttherapy (e.g., interrupted treatment, intermittent treatment, treatmentat relapse, or treatment upon achievement of a particular predeterminedcriteria [e.g., pain, disease manifestation, etc.]). Delivery of anIL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof) during a maintenance regimen may be via a subcutaneous route,e.g., delivery of dosages of about 75 mg-about 300 mg s.c. (e.g., about75 mg s.c., about 150 mg s.c., about 300 mg s.c.), or via an intravenousroute, e.g., delivery of dosages of about 1 mg/kg-about 30 mg/kg i.v.(e.g., about 1 mg/kg, about 3 mg/kg, about 10 mg/kg, about 30 mg/kg), orany other route of administration (e.g, intramuscular, i.m.). In someembodiments of the disclosed methods, uses and regimens, the IL-17antagonist (e.g., secukinumab) is delivered by s.c. administrationduring the maintenance regimen. In some embodiments, the maintenanceregimen comprises administering a dose of about 75 mg-about 300 mg,about 75 mg-about 150 mg, preferably about 75 mg or about 150 mg of theIL-17 antagonist (e.g., secukinumab). In some embodiments, themaintenance regimen comprises administering a dose of the IL-17antagonist (e.g., secukinumab) on a monthly basis.

A maintenance regimen for delivery of an IL-17 antagonist, e.g., anIL-17 binding molecule (e.g., an IL-17 antibody, such as secukinumab) oran IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody)may also be designed using PK information (see Table 9), rather thanspecific dosages. For the disclosed uses, regimens and methods (e.g.,methods of treating an inflammatory arthridities, e.g., RA, such as ahigh risk RA patient), an artisan may deliver an IL-17 antagonist, e.g.,an IL-17 binding molecule (e.g., an IL-17 antibody, such as secukinumab)or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody)during a maintenance regimen to provide an average steady-state troughlevel of about 9.4 μg/mL-about 31 μg/mL (e.g., about 9.4 μg/mL, about17.3 μg/mL, about 31 μg/mL), with up to about a 30% [+ or −]inter-patient variation for an average 75 kg (e.g., 71-79 kg) human.Alternatively, an artisan may deliver an IL-17 antagonist, e.g., anIL-17 binding molecule (e.g., an IL-17 antibody, such as secukinumab) oran IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody)during a maintenance regimen to provide an average steady-state troughlevel of about 8.0 μg/mL-about 30.0 μg/mL (e.g., about 8.0 μg/mL, about17 μg/mL, about 30 μg/mL) for an average 75 kg human. In someembodiments, the IL-17 antagonist is delivered monthly during amaintenance regimen to provide an average steady-state trough level ofabout 9.4 μg/mL-about 31 μg/mL (e.g., about 9.4 μg/mL, about 17.3 μg/mL,about 31 μg/mL), with up to about a 30% [+ or −] inter-patient variationfor an average 70 kg human. In other embodiments, the IL-17 antagonistis delivered monthly during a maintenance regimen to provide an averagesteady-state trough level of about 8.0 μg/mL-about 30.0 μg/mL (e.g.,about 8.0 μg/mL, about 17 μg/mL, about 30 μg/mL) for an average 75 kghuman. Alternatively, an artisan may deliver an IL-17 antagonist, e.g.,an IL-17 binding molecule (e.g., an IL-17 antibody, such as secukinumab)or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody)during a maintenance regimen to provide a mean AUC tau at steady stateof about 314 mg*day/L-about 1323 mg*day/L (e.g., about 314 mg*day/L toabout 1256 mg*day/L, e.g., about 331 mg*day/L to about 1323 mg*day/L).

The timing of dosing is generally measured from the day of the firstdose of secukinumab (which is also known as “baseline”). However,different health care providers use different naming conventions, asshown in Table 3, below.

TABLE 3 Common naming conventions for dosing regimens. Bolded itemsrefer to the naming convention used herein. Week 0/1 1/2 2/3 3/4 4/5 5/66/7 7/8 8/9  9/10 10/11 etc 1^(st) day 0/1 7/8 14/15 21/22 28/29 35/3642/43 49/50 56/57 63/64 70/71 etc.

Notably, week zero may be referred to as week one in some namingconventions, while day zero may be referred to as day one in some namingconventions. Thus, it is possible that different physicians willdesignate, e.g., a dose as being given during week 3/on day 21, duringweek 3/on day 22, during week 4/on day 21, during week 4/on day 22,while referring to the same dosing schedule. For consistency, as usedherein, the first week of dosing will be referred to as week zero, whilethe first day of dosing will be referred to as day 1. Thus, as anexample, four induction doses of secukinumab administered weekly duringan induction regimen would be provided during week 0 (e.g., on about day1), during week 1 (e.g., on about day 8), during week 2 (e.g., on aboutday 15), and during week 3 (e.g., on about day 22). Induction doses maybe administered every two weeks (i.e., every other week), e.g., duringweek 0, during week 2, during week 4, etc. Induction doses may beadministered every three weeks, e.g., during week 0, during week 3,during week 6, etc. Induction doses may be administered daily for oneweek, e.g., on day 1-7. It must be noted, however, that this namingconvention is only used for clarity, and should not be construed aslimiting.

As used herein, the phrase “means for administering” is used to indicateany available implement for systemically administering a biologic,including, but not limited to, a pre-filled syringe, a vial and syringe,an injection pen, an autoinjector, an i.v. drip and bag, a pump, etc.With such items, a patient may self-administer the drug (i.e.,administer the drug on their own behalf) or a physician may administerthe drug.

Various aspects of the disclosure are described in further detail in thefollowing subsections. All patents, patent applications, references andother publications are incorporated by reference herein in theirentirety.

IL-17 Antagonists

The various disclosed pharmaceutical compositions, regimens, processes,uses, methods and kits utilize an IL-17 antagonist, e.g., IL-17 bindingmolecule (e.g., IL-17 antibody or antigen binding fragment thereof,e.g., secukinumab) or IL-17 receptor binding molecule (e.g., IL-17antibody or antigen binding fragment thereof).

In one embodiment, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises at least one immunoglobulin heavy chain variabledomain (V_(H)) comprising in sequence hypervariable regions CDR1, CDR2and CDR3, said CDR1 having the amino acid sequence SEQ ID NO:1(N-Y-W-M-N), said CDR2 having the amino acid sequence SEQ ID NO:2(A-I-N-Q-D-G-S-E-K-Y-Y-V-G-S-V-K-G), and said CDR3 having the amino acidsequence SEQ ID NO:3 (D-Y-Y-D-I-L-T-D-Y-Y-I-H-Y-W-Y-F-D-L).

In one embodiment, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises at least one immunoglobulin light chain variabledomain (V_(L)) comprising in sequence hypervariable regions CDR1′, CDR2′and CDR3′, said CDR1′ having the amino acid sequence SEQ ID NO:4(R-A-S-Q-S-V-S-S-S-Y-L-A), said CDR2′ having the amino acid sequence SEQID NO:5 (G-A-S-S-R-A-T) and said CDR3′ having the amino acid sequenceSEQ ID NO:6 (Q-Q-Y-G-S-S-P-C-T).

In one embodiment, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises at least one immunoglobulin heavy chain variabledomain (V_(H)) comprising in sequence hypervariable regions CDR1-x,CDR2-x and CDR3-x, said CDR1-x having the amino acid sequence SEQ IDNO:11 (G-F-T-F-S-N-Y-W-M-N), said CDR2-x having the amino acid sequenceSEQ ID NO:12 (A-I-N-Q-D-G-S-E-K-Y-Y), and said CDR3-x having the aminoacid sequence SEQ ID NO:13(C-V-R-D-Y-Y-D-I-L-T-D-Y-Y-I-H-Y-W-Y-F-D-L-W-G).

In one embodiment, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises at least one immunoglobulin V_(H) domain and atleast one immunoglobulin V_(L) domain, wherein: a) the immunoglobulinV_(H) domain comprises: i) hypervariable regions CDR1, CDR2 and CDR3,said CDR1 having the amino acid sequence SEQ ID NO:1, said CDR2 havingthe amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acidsequence SEQ ID NO:3; or ii) hypervariable regions CDR1-x, CDR2-x andCDR3-x, said CDR1-x having the amino acid sequence SEQ ID NO:11, saidCDR2-x having the amino acid sequence SEQ ID NO:12, and said CDR3-xhaving the amino acid sequence SEQ ID NO:13; and b) the immunoglobulinV_(L) domain comprises hypervariable regions CDR1′, CDR2′ and CDR3′,said CDR1′ having the amino acid sequence SEQ ID NO:4, said CDR2′ havingthe amino acid sequence SEQ ID NO:5, and said CDR3′ having the aminoacid sequence SEQ ID NO:6 or.

In one embodiment, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises at least one immunoglobulin V_(H) domain and atleast one immunoglobulin V_(L) domain, wherein: a) the at least oneimmunoglobulin V_(H) domain comprises in sequence hypervariable regionsCDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence SEQ IDNO:1, said CDR2 having the amino acid sequence SEQ ID NO:2, and saidCDR3 having the amino acid sequence SEQ ID NO:3; and b) the at least oneimmunoglobulin V_(L) domain comprises in sequence hypervariable regionsCDR1′, CDR2′ and CDR3′, said CDR1′ having the amino acid sequence SEQ IDNO:4, said CDR2′ having the amino acid sequence SEQ ID NO:5, and saidCDR3′ having the amino acid sequence SEQ ID NO:6.

In one embodiment, t the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises at least one immunoglobulin V_(H) domain and atleast one immunoglobulin V_(L) domain, wherein: a) the at least oneimmunoglobulin V_(H) domain comprises in sequence hypervariable regionsCDR1-x, CDR2-x and CDR3-x, said CDR1-x having the amino acid sequenceSEQ ID NO:11, said CDR2-x having the amino acid sequence SEQ ID NO:12,and said CDR3-x having the amino acid sequence SEQ ID NO:13; and b) theat least one immunoglobulin V_(L) domain comprises in sequencehypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ having theamino acid sequence SEQ ID NO:4, said CDR2′ having the amino acidsequence SEQ ID NO:5, and said CDR3′ having the amino acid sequence SEQID NO:6.

In one embodiment, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises: a) an immunoglobulin heavy chain variabledomain (V_(H)) comprising the amino acid sequence set forth as SEQ IDNO:8; b) an immunoglobulin light chain variable domain (V_(L))comprising the amino acid sequence set forth as SEQ ID NO:10; c) animmunoglobulin V_(H) domain comprising the amino acid sequence set forthas SEQ ID NO:8 and an immunoglobulin V_(L) domain comprising the aminoacid sequence set forth as SEQ ID NO:10; d) an immunoglobulin V_(H)domain comprising the hypervariable regions set forth as SEQ ID NO:1,SEQ ID NO:2, and SEQ ID NO:3 e) an immunoglobulin V_(L) domaincomprising the hypervariable regions set forth as SEQ ID NO:4, SEQ IDNO:5 and SEQ ID NO:6; f) an immunoglobulin V_(H) domain comprising thehypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ IDNO:13; g) an immunoglobulin V_(H) domain comprising the hypervariableregions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and animmunoglobulin V_(L) domain comprising the hypervariable regions setforth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; or h) animmunoglobulin V_(H) domain comprising the hypervariable regions setforth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 and animmunoglobulin V_(L) domain comprising the hypervariable regions setforth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.

For ease of reference the amino acid sequences of the hypervariableregions of the secukinumab monoclonal antibodies, based on the Kabatdefinition and as determined by the X-ray analysis and using theapproach of Chothia and coworkers, is provided in Table 4, below.

TABLE 4 Amino acid sequences of the hypervariableregions of the secukinumab monoclonal antibodies. Light-chain CDR1′Kabat R-A-S-Q-S-V-S-S-S-Y-L-A (SEQ ID NO: 4) Chothia/R-A-S-Q-S-V-S-S-S-Y-L-A X-ray (SEQ ID NO: 4) CDR2′ Kabat G-A-S-S-R-A-T(SEQ ID NO: 5) Chothia/ G-A-S-S-R-A-T X-ray (SEQ ID NO: 5) CDR3′ KabatQ-Q-Y-G-S-S-P-C-T (SEQ ID NO: 6) Chothia/ Q-Q-Y-G-S-S-P-C-T X-ray(SEQ ID NO: 6) Heavy-chain CDR1 Kabat N-Y-W-M-N (SEQ ID NO: 1) CDR1-xChothia/ G-F-T-F-S-N-Y-W-M-N X-ray (SEQ ID NO: 11) CDR2 KabatA-I-N-Q-D-G-S-E-K-Y-Y-V- G-S-V-K-G (SEQ ID NO: 2) CDR2-x Chothia/A-I-N-Q-D-G-S-E-K-Y-Y X-ray (SEQ ID NO: 12) CDR3 KabatD-Y-Y-D-I-L-T-D-Y-Y-I-H- Y-W-Y-F-D-L (SEQ ID NO: 3) CDR3-x Chothia/C-V-R-D-Y-Y-D-I-L-T-D-Y- X-ray Y-I-H-Y-W-Y-F-D-L-W-G (SEQ ID NO: 13)Amino acid highlighted in bold are part of the CDR loops, while thoseshown in plain style are part of the antibody framework.

In preferred embodiments, the variable domains of both heavy and lightchains are of human origin, for instance those of the secukinumabantibody which are shown in SEQ ID NO:10 (=variable domain of lightchain, i.e., amino acid 1 to 109 of SEQ ID NO:10) and SEQ ID NO:8(=variable domain of heavy chain, i.e., amino acid 1 to 127 of SEQ IDNO:8). The constant region domains preferably also comprise suitablehuman constant region domains, for instance as described in “Sequencesof Proteins of Immunological Interest”, Kabat E. A. et al, US Departmentof Health and Human Services, Public Health Service, National Instituteof Health.

In some embodiments, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises the variable light domain of SEQ ID NO:10. Inother embodiments, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises the variable heavy domain of SEQ ID NO:8. Inother embodiments, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises the variable light domain of SEQ ID NO:10 andthe variable heavy domain of SEQ ID NO:8. In some embodiments, the IL-17antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab), comprises thethree CDRs of SEQ ID NO:10. In other embodiments, the IL-17 antagonist,e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen bindingfragment thereof, e.g., secukinumab), comprises the three CDRs of SEQ IDNO:8. In other embodiments, an the IL-17 antagonist, e.g., IL-17 bindingmolecule (e.g., IL-17 antibody or antigen binding fragment thereof,e.g., secukinumab), comprises the three CDRs of SEQ ID NO:10 and thethree CDRs of SEQ ID NO:8. CDRs of SEQ ID NO:8 and SEQ ID NO:10,according to both the Chothia and Kabat definition, may be found inTable 4.

In some embodiments, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises the light domain of SEQ ID NO:15. In otherembodiments, the IL-17 antagonist, e.g., IL-17 binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab),comprises the heavy domain of SEQ ID NO:17. In other embodiments, theIL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab), comprises thelight domain of SEQ ID NO:15 and the heavy domain of SEQ ID NO:17. Insome embodiments, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab), comprises the three CDRs of SEQ ID NO:15. In otherembodiments, the IL-17 antagonist, e.g., IL-17 binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab),comprises the three CDRs of SEQ ID NO:17. In other embodiments, theIL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab), comprises thethree CDRs of SEQ ID NO:15 and the three CDRs of SEQ ID NO:17. CDRs ofSEQ ID NO:15 and SEQ ID NO:17, according to both the Chothia and Kabatdefinition, may be found in Table 4.

Hypervariable regions may be associated with any kind of frameworkregions, though preferably are of human origin. Suitable frameworkregions are described in Kabat E. A. et al, ibid. The preferred heavychain framework is a human heavy chain framework, for instance that ofthe secukinumab antibody. It consists in sequence, e.g., of FR1 (aminoacid 1 to 30 of SEQ ID NO:8), FR2 (amino acid 36 to 49 of SEQ ID NO:8),FR3 (amino acid 67 to 98 of SEQ ID NO:8) and FR4 (amino acid 117 to 127of SEQ ID NO:8) regions. Taking into consideration the determinedhypervariable regions of secukinumab by X-ray analysis, anotherpreferred heavy chain framework consists in sequence of FR1-x (aminoacid 1 to 25 of SEQ ID NO:8), FR2-x (amino acid 36 to 49 of SEQ IDNO:8), FR3-x (amino acid 61 to 95 of SEQ ID NO:8) and FR4 (amino acid119 to 127 of SEQ ID NO:8) regions. In a similar manner, the light chainframework consists, in sequence, of FR1′ (amino acid 1 to 23 of SEQ IDNO:10), FR2′ (amino acid 36 to 50 of SEQ ID NO:10), FR3′ (amino acid 58to 89 of SEQ ID NO:10) and FR4′ (amino acid 99 to 109 of SEQ ID NO:10)regions.

In one embodiment, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab) is selected from a human anti-IL-17 antibody, whichcomprises at least: a) an immunoglobulin heavy chain or fragment thereofwhich comprises a variable domain comprising in sequence thehypervariable regions CDR1, CDR2 and CDR3 and the constant part orfragment thereof of a human heavy chain; said CDR1 having the amino acidsequence SEQ ID NO:1, said CDR2 having the amino acid sequence SEQ IDNO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3; and b)an immunoglobulin light chain or fragment thereof, which comprises avariable domain comprising in sequence the hypervariable regions CDR1′,CDR2′, and CDR3′ and the constant part or fragment thereof of a humanlight chain, said CDR1′ having the amino acid sequence SEQ ID NO: 4,said CDR2′ having the amino acid sequence SEQ ID NO:5, and said CDR3′having the amino acid sequence SEQ ID NO:6.

In one embodiment, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab) is selected from a single chain binding molecule, whichcomprises an antigen binding site comprising: a) a first domaincomprising in sequence the hypervariable regions CDR1, CDR2 and CDR3,said CDR1 having the amino acid sequence SEQ ID NO:1, said CDR2 havingthe amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acidsequence SEQ ID NO:3; and b) a second domain comprising thehypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ having theamino acid sequence SEQ ID NO:4, said CDR2′ having the amino acidsequence SEQ ID NO:5, and said CDR3′ having the amino acid sequence SEQID NO:6; and c) a peptide linker which is bound either to the N-terminalextremity of the first domain and to the C-terminal extremity of thesecond domain or to the C-terminal extremity of the first domain and tothe N-terminal extremity of the second domain.

Alternatively, the IL-17 antagonist, e.g., IL-17 binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab)may comprise at least one antigen binding site comprising at least oneimmunoglobulin heavy chain variable domain (V_(H)) which comprises insequence: a) hypervariable regions CDR1 (SEQ ID NO:1), CDR2 (SEQ IDNO:2) and CDR3 (SEQ ID NO:3); or b) hypervariable regions CDR1_(i),CDR2_(i), CDR3, said hypervariable region CDR1_(i) differs by 3,preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR1 as shown in SEQ ID NO:1, said hypervariable regionCDR2_(i) differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR2 as shown in SEQ ID NO:2; and saidhypervariable region CDR3_(i) differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR3 asshown in SEQ ID NO:3; and said binding IL-17 molecule is capable ofinhibiting the activity of about 1 nM (=30 ng/ml) human IL-17 at aconcentration of about 50 nM or less, about 20 nM or less, about 10 nMor less, about 5 nM or less, about 2 nM or less, or more preferably ofabout 1 nM or less of said molecule by 50%, said inhibitory activitybeing measured on IL-6 production induced by hu-IL-17 in human dermalfibroblasts.

Similarly, the IL-17 antagonist, e.g., IL-17 binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab)may comprise at least one antigen binding site comprising at least oneimmunoglobulin heavy chain variable domain (V_(H)) which comprises insequence: a) hypervariable regions CDR1-x (SEQ ID NO:11), CDR2-x (SEQ IDNO:12) and CDR3-x (SEQ ID NO:13); or b) hypervariable regionsCDR1_(i)-x, CDR2_(i)-x, CDR3_(i)-x, said hypervariable region CDR1_(i)-xdiffers by 3, preferably 2, more preferably 1 amino acid(s) from thehypervariable region of CDR1-x as shown in SEQ ID NO: 11, saidhypervariable region CDR2_(i)-x differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR2-x asshown in SEQ ID NO:12; and said hypervariable region CDR3_(i)-x differsby 3, preferably 2, more preferably 1 amino acid(s) from thehypervariable region of CDR3-x as shown in SEQ ID NO:13; and saidbinding IL-17 molecule is capable of inhibiting the activity of 1 nM(=30 ng/ml) human IL-17 at a concentration of about 50 nM or less, about20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM orless, or more preferably of about 1 nM or less of said molecule by 50%,said inhibitory activity being measured on IL-6 production induced byhu-IL-17 in human dermal fibroblasts.

Similarly, the IL-17 antagonist, e.g., IL-17 binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab)may comprise at least one antigen binding site comprising at least oneimmunoglobulin light chain variable domain (V_(L)) which comprises insequence: a) hypervariable regions CDR′1 (SEQ ID NO:4), CDR′2 (SEQ IDNO:5) and CDR′3 (SEQ ID NO:6); orb) hypervariable regions CDR1′_(i),CDR2′_(i), CDR3′_(i), said hypervariable region CDR′1_(i) differs by 3,preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR′1 as shown in SEQ ID NO:4, said hypervariable regionCDR′2_(i) differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR′2 as shown in SEQ ID NO:5; and saidhypervariable region CDR′3_(i) differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR′3 asshown in SEQ ID NO:6; and said binding IL-17 molecule is capable ofinhibiting the activity of 1 nM (=30 ng/ml) human IL-17 at aconcentration of about 50 nM or less, about 20 nM or less, about 10 nMor less, about 5 nM or less, about 2 nM or less, or more preferably ofabout 1 nM or less of said molecule by 50%, said inhibitory activitybeing measured on IL-6 production induced by hu-IL-17 in human dermalfibroblasts.

Alternatively, the IL-17 antagonist, e.g., IL-17 binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab)may comprise both heavy (V_(H)) and light chain (V_(L)) variable domainsand said IL-17 binding molecule having at least one antigen binding sitecomprising: a) an immunoglobulin heavy chain variable domain (V_(H))which comprises in sequence hypervariable regions CDR1 (SEQ ID NO:1),CDR2 (SEQ ID NO:2) and CDR3 (SEQ ID NO:); and an immunoglobulin lightchain variable domain (V_(L)) which comprises in sequence hypervariableregions CDR1′ (SEQ ID NO:4), CDR2′ (SEQ ID NO:5) and CDR3′ (SEQ IDNO:6); or b) an immunoglobulin heavy chain variable domain (V_(H)) whichcomprises in sequence hypervariable regions CDR1_(i), CDR2_(i), andCDR3_(i), said hypervariable region CDR1_(i) differs by 3, preferably 2,more preferably 1 amino acid(s) from the hypervariable region of CDR1 asshown in SEQ ID NO:1, said hypervariable region CDR2_(i) differs by 3,preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR2 as shown in SEQ ID NO:2; and said hypervariable regionCDR3_(i) differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR3 as shown in SEQ ID NO:3; and animmunoglobulin light chain variable domain (V_(L)) which comprises insequence hypervariable regions CDR1′_(i), CDR2′_(i), CDR3′_(i), saidhypervariable region CDR′1_(i) differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR′1 asshown in SEQ ID NO:4, said hypervariable region CDR′2_(i) differs by 3,preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR′2 as shown in SEQ ID NO:5; and said hypervariable regionCDR′3_(i) differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR′3 as shown in SEQ ID NO:6; and saidbinding IL-17 molecule is capable of inhibiting the activity of 1 nM(=30 ng/ml) human IL-17 at a concentration of about 50 nM or less, about20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM orless, or more preferably of about 1 nM or less of said molecule by 50%,said inhibitory activity being measured on IL-6 production induced byhu-IL-17 in human dermal fibroblasts.

Alternatively, the IL-17 antagonist, e.g., IL-17 binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab)may comprise both heavy (V_(H)) and light chain (V_(L)) variable domainsand said IL-17 binding molecule comprises at least one antigen bindingsite comprising: a) an immunoglobulin heavy chain variable domain(V_(H)) which comprises in sequence hypervariable regions CDR1-x (SEQ IDNO:11), CDR2-x (SEQ ID NO:12) and CDR3-x (SEQ ID NO:13); and animmunoglobulin light chain variable domain (V_(L)) which comprises insequence hypervariable regions CDR1′ (SEQ ID NO:4), CDR2′ (SEQ ID NO: 5)and CDR3′ (SEQ ID NO:6); or b) an immunoglobulin heavy chain variabledomain (V_(H)) which comprises in sequence hypervariable regionsCDR1_(i)-x, CDR2_(i)-x, and CDR3_(i)-x, said hypervariable regionhypervariable regions CDR1_(i)-x, CDR2_(i)-x, CDR3_(i)-x, saidhypervariable region CDR1_(i)-x differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR1-x asshown in SEQ ID NO: 11, said hypervariable region CDR2_(i)-x differs by3, preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR2-x as shown in SEQ ID NO:12; and said hypervariable regionCDR3_(i)-x differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR3-x as shown in SEQ ID NO: 13; andan immunoglobulin light chain variable domain (V_(L)) which comprises insequence hypervariable regions CDR1′_(i), CDR2′_(i), CDR3′_(i), saidhypervariable region CDR′1_(i) differs by 3, preferably 2, morepreferably 1 amino acid(s) from the hypervariable region of CDR′1 asshown in SEQ ID NO: 4, said hypervariable region CDR′2_(i) differs by 3,preferably 2, more preferably 1 amino acid(s) from the hypervariableregion of CDR′2 as shown in SEQ ID NO:5; and said hypervariable regionCDR′3_(i) differs by 3, preferably 2, more preferably 1 amino acid(s)from the hypervariable region of CDR′3 as shown in SEQ ID NO:6; and saidbinding IL-17 molecule is capable of inhibiting the activity of 1 nM(=30 ng/ml) human IL-17 at a concentration of about 50 nM or less, about20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM orless, or more preferably of about 1 nM or less of said molecule by 50%,said inhibitory activity being measured on IL-6 production induced byhu-IL-17 in human dermal fibroblasts.

A human IL-17 antibody disclosed herein may comprise a heavy chain thatis substantially identical to that set forth as SEQ ID NO:17 and a lightchain that is substantially identical to that set forth as SEQ ID NO:15.A human IL-17 antibody disclosed herein may comprise a heavy chain thatcomprises SEQ ID NO:17 and a light chain that comprises SEQ ID NO:15.

A human IL-17 antibody disclosed herein may comprise: a) one heavy chainwhich comprises a variable domain having an amino acid sequencesubstantially identical to that shown in SEQ ID NO:8 and the constantpart of a human heavy chain; and b) one light chain which comprises avariable domain having an amino acid sequence substantially identical tothat shown in SEQ ID NO:10 and the constant part of a human light chain.

The inhibition of the binding of IL-17 to its receptor may beconveniently tested in various assays including such assays as describedin WO 2006/013107. By the term “to the same extent” is meant that thereference and the derivative molecules exhibit, on a statistical basis,essentially identical IL-17 inhibitory activity in one of the assaysreferred to herein (see Example 1 of WO 2006/013107). For example, theIL-17 binding molecules disclosed herein typically have IC₅₀s for theinhibition of human IL-17 on IL-6 production induced by human IL-17 inhuman dermal fibroblasts which are below about 10 nM, more preferablyabout 9, 8, 7, 6, 5, 4, 3, 2, or about 1 nM of that of, preferablysubstantially the same as, the IC₅₀ of the corresponding referencemolecule when assayed as described in Example 1 of WO 2006/013107.Alternatively, the assay used may be an assay of competitive inhibitionof binding of IL-17 by soluble IL-17 receptors (e.g. the human IL-17R/Fc constructs of Example 1 of WO 2006/013107) and the IL-17 bindingmolecules of the disclosure.

The disclosure also includes IL-17 antagonists, e.g., IL-17 bindingmolecules (e.g., IL-17 antibody or antigen binding fragment thereof,e.g., secukinumab) in which one or more of the amino acid residues ofCDR1, CDR2, CDR3, CDR1-x, CDR2-x, CDR3-x, CDR1′, CDR2′ or CDR3′ or theframeworks, typically only a few (e.g., 1-4), are changed; for instanceby mutation, e.g., site directed mutagenesis of the corresponding DNAsequences. The disclosure includes the DNA sequences coding for suchchanged IL-17 binding molecules. In particular the disclosure includesIL-17 binding molecules in which one or more residues of CDR1′ or CDR2′have been changed from the residues shown in SEQ ID NO:4 (for CDR1′) andSEQ ID NO:5 (for CDR2′).

The disclosure also includes IL-17 antagonists, e.g., IL-17 bindingmolecules (e.g., IL-17 antibody or antigen binding fragment thereof,e.g., secukinumab) that have binding specificity for human IL-17, inparticular IL-17 antibodies capable of inhibiting the binding of IL-17to its receptor and IL-17 antibodies capable of inhibiting the activityof 1 nM (=30 ng/ml) human IL-17 at a concentration of about 50 nM orless, about 20 nM or less, about 10 nM or less, about 5 nM or less,about 2 nM or less, or more preferably of about 1 nM or less of saidmolecule by 50% (said inhibitory activity being measured on IL-6production induced by hu-IL-17 in human dermal fibroblasts).

The disclosure provides methods for treating RA, comprisingadministering a therapeutically effective amount of an IL-17 antagonist,e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen bindingfragment thereof, e.g., secukinumab) to a subject suffering from RA,e.g., a high risk RA patient. In some embodiments, the IL-17 antibody,e.g., secukinumab, binds to an epitope of mature human IL-17 comprisingLeu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127,Val128, His129. In some embodiments, the IL-17 antibody, e.g.,secukinumab, binds to an epitope of mature human IL-17 comprising Tyr43,Tyr44, Arg46, Ala79, Asp80. In some embodiments, the IL-17 antibody,e.g., secukinumab, binds to an epitope of an IL-17 homodimer having twomature human IL-17 chains, said epitope comprising Leu74, Tyr85, His86,Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on onechain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain. Theresidue numbering scheme used to define these epitopes is based onresidue one being the first amino acid of the mature protein (ie.,IL-17A lacking the 23 amino acid N-terminal signal peptide and beginningwith Glycine). The sequence for immature IL-17A is set forth in theSwiss-Prot entry Q16552.

In some embodiments, the IL-17 antibody has a K_(D) of about 100-200 pM.In some embodiments, the IL-17 antibody has an IC₅₀ of about 0.4 nM forin vitro neutralization of the biological activity of about 0.67 nMhuman IL-17A. In some embodiments, the absolute bioavailability ofsubcutaneously (s.c.) administered IL-17 antibody has a range of about60-about 80%, e.g., about 76%. In some embodiments, the IL-17antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody,such as secukinumab) or an IL-17 receptor binding molecule (e.g., anIL-17 receptor antibody) has an elimination half-life of about 4 weeks(e.g., about 23 to about 30 days, e.g., about 30 days). In someembodiments, the IL-17 antagonist, e.g., an IL-17 binding molecule(e.g., an IL-17 antibody, such as secukinumab) or an IL-17 receptorbinding molecule (e.g., an IL-17 receptor antibody) has a T_(max) ofabout 7-8 days.

In some embodiments of the disclosed methods, uses, pharmaceuticalcompositions, kits, assays, and treatment regimens, the IL-17 antagonistis selected from the group consisting of: a) an IL-17 binding moleculeor an IL-17 receptor binding molecule; b) secukinumab; c) an IL-17antibody that binds to an epitope of IL-17 comprising Leu74, Tyr85,His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129; d)an IL-17 antibody that binds to an epitope of IL-17 comprising Tyr43,Tyr44, Arg46, Ala79, Asp80; e) an IL-17 antibody that binds to anepitope of an IL-17 homodimer having two mature IL-17 protein chains,said epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124,Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44,Arg46, Ala79, Asp80 on the other chain; f) an IL-17 antibody that bindsto an epitope of an IL-17 homodimer having two mature IL-17 proteinchains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88,Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43,Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 bindingmolecule has a K_(D) of about 100-200 pM, and wherein the IL-17 bindingmolecule has an in vivo half-life of about 4 weeks; and g) an IL-17antibody that comprises an antibody selected from the group consistingof: i) an immunoglobulin heavy chain variable domain (V_(H)) comprisingthe amino acid sequence set forth as SEQ ID NO:8; ii) an immunoglobulinlight chain variable domain (V_(L)) comprising the amino acid sequenceset forth as SEQ ID NO:10; iii) an immunoglobulin V_(H) domaincomprising the amino acid sequence set forth as SEQ ID NO:8 and animmunoglobulin V_(L) domain comprising the amino acid sequence set forthas SEQ ID NO:10; iv) an immunoglobulin V_(H) domain comprising thehypervariable regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ IDNO:3; v) an immunoglobulin V_(L) domain comprising the hypervariableregions set forth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; vi) animmunoglobulin V_(H) domain comprising the hypervariable regions setforth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13; vii) animmunoglobulin V_(H) domain comprising the hypervariable regions setforth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and an immunoglobulinV_(L) domain comprising the hypervariable regions set forth as SEQ IDNO:4, SEQ ID NO:5 and SEQ ID NO:6; and viii) an immunoglobulin V_(H)domain comprising the hypervariable regions set forth as SEQ ID NO:11,SEQ ID NO:12 and SEQ ID NO:13 and an immunoglobulin V_(L) domaincomprising the hypervariable regions set forth as SEQ ID NO:4, SEQ IDNO:5 and SEQ ID NO:6.

Particularly preferred IL-17 antagonists, e.g., IL-17 binding molecules(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 antibodyor antigen binding fragment thereof) for use in the disclosed methods,uses, kits, etc. are human antibodies, especially secukinumab asdescribed in Examples 1 and 2 of WO 2006/013107. Secukinumab (AIN457) isa recombinant high-affinity, fully human monoclonal anti-humaninterleukin-17A (IL-17A, IL-17) antibody of the IgG1/kappa isotype.Secukinumab (see, e.g., WO2006/013107 and WO2007/117749) has a very highaffinity for IL-17, i.e., a K_(D) of about 100-200 pM and an IC₅₀ for invitro neutralization of the biological activity of about 0.67 nM humanIL-17A of about 0.4 nM. Thus, secukinumab inhibits antigen at a molarratio of about 1:1. This high binding affinity makes the secukinumabantibody particularly suitable for therapeutic applications.Furthermore, it has been determined that secukinumab has a very longhalf life, i.e., about 4 weeks, which allows for prolonged periodsbetween administration, an exceptional property when treating chroniclife-long disorders, such as rheumatoid arthritis (RA).

Treatment Regimens, Methods of Treatment, Pharmaceutical Compositionsand Uses

The disclosed IL-17 antagonists, e.g., IL-17 binding molecules (e.g.,IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab)or IL-17 receptor binding molecules (e.g., IL-17 antibody or antigenbinding fragment thereof) are useful for the treatment, prevention, oramelioration of inflammatory arthritis (e.g., rheumatoid arthritis (RA),spondyloarthropathy, ankylosing spondylitis, and psoriatic arthritis).Thus, such molecules are useful in inducing changes in the signs andsymptoms of arthritis & structural changes, preventing further jointerosion, improving joint structure, etc. In some embodiments, thepatient having inflammatory arthritis is an RA patient, e.g., a highrisk RA patient.

The IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17antibody or antigen binding fragment thereof, e.g., secukinumab) orIL-17 receptor binding molecules (e.g., IL-17 antibody or antigenbinding fragment thereof) may be used in vitro, ex vivo, or incorporatedinto pharmaceutical compositions and administered to individuals (e.g.,human subjects) in vivo to treat, ameliorate, or prevent RA, e.g., inhigh risk RA patients. A pharmaceutical composition will be formulatedto be compatible with its intended route of administration (e.g., oralcompositions generally include an inert diluent or an edible carrier).Other nonlimiting examples of routes of administration includeparenteral (e.g., intravenous), intradermal, subcutaneous, oral (e.g.,inhalation), transdermal (topical), transmucosal, and rectaladministration. The pharmaceutical compositions compatible with eachintended route are well known in the art.

The IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17antibody or antigen binding fragment thereof, e.g., secukinumab) orIL-17 receptor binding molecules (e.g., IL-17 antibody or antigenbinding fragment thereof) may be used as a pharmaceutical compositionwhen combined with a pharmaceutically acceptable carrier. Such acomposition may contain, in addition to an IL-17 antagonist (e.g.,secukinumab) carriers, various diluents, fillers, salts, buffers,stabilizers, solubilizers, and other materials well known in the art.The characteristics of the carrier will depend on the route ofadministration.

The pharmaceutical compositions for use in the disclosed methods mayalso contain additional therapeutic agents for treatment of theparticular targeted disorder. For example, a pharmaceutical compositionmay also include anti-inflammatory agents. Such additional factorsand/or agents may be included in the pharmaceutical composition toproduce a synergistic effect with the IL-17 antagonist (e.g.,secukinumab), or to minimize side effects caused by the IL-17 bindingmolecules.

The pharmaceutical composition of the disclosure may be in the form of aliposome in which the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof) is combined, in addition to otherpharmaceutically acceptable carriers, with amphipathic agents such aslipids that exist in aggregated form as micelles, insoluble monolayers,liquid crystals, or lamellar layers in aqueous solution. Suitable lipidsfor liposomal formulation include, without limitation, monoglycerides,diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bileacids, etc.

In practicing the methods of treatment, regimen, uses, etc. of thepresent disclosure, a therapeutically effective amount of an IL-17antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof) is administered to a subject, e.g., a mammal (e.g., a human).An IL-17 antagonist (e.g., secukinumab) may be administered inaccordance with the method of the disclosure either alone or incombination with other therapies, such as, e.g., in combination withadditional therapies for inflammation. When coadministered with one ormore agents, an IL-17 antagonist (e.g., secukinumab) may be administeredeither simultaneously with the other agent, or sequentially. Ifadministered sequentially, the attending physician will decide on theappropriate sequence of administering the IL-17 antagonist (e.g.,secukinumab) in combination with other agents.

When a therapeutically effective amount of an IL-17 antagonist, e.g.,IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof) is administeredorally, the binding agent will be in the form of a tablet, capsule,powder, solution or elixir. When administered in tablet form, thepharmaceutical composition of the disclosure may additionally contain asolid carrier such as a gelatin or an adjuvant. When administered inliquid form, a liquid carrier such as water, petroleum, oils of animalor plant origin such as peanut oil (exercising caution in relation topeanut allergies), mineral oil, soybean oil, or sesame oil, or syntheticoils may be added. The liquid form of the pharmaceutical composition mayfurther contain components such as physiological saline solution,dextrose or other saccharide solution, or glycols such as ethyleneglycol, propylene glycol, or polyethylene glycol.

When a therapeutically effective amount of an IL-17 antagonist, e.g.,IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof) is administered byintravenous, cutaneous or subcutaneous injection, the IL-17 bindingmolecule will be in the form of a pyrogen-free, parenterally acceptablesolution. A pharmaceutical composition for intravenous, cutaneous, orsubcutaneous injection may contain, in addition to the IL-17 antagonist(e.g., secukinumab), an isotonic vehicle such as sodium chloride,Ringer's, dextrose, dextrose and sodium chloride, lactated Ringer's, orother vehicle as known in the art.

Pharmaceutical compositions for use in the disclosed methods may bemanufactured in conventional manner. In one embodiment, thepharmaceutical composition is preferably provided in lyophilized form.For immediate administration it is dissolved in a suitable aqueouscarrier, for example sterile water for injection or sterile bufferedphysiological saline. If it is considered desirable to make up asolution of larger volume for administration by infusion rather than abolus injection, may be advantageous to incorporate human serum albuminor the patient's own heparinised blood into the saline at the time offormulation. The presence of an excess of such physiologically inertprotein prevents loss of antibody by adsorption onto the walls of thecontainer and tubing used with the infusion solution. If albumin isused, a suitable concentration is from 0.5 to 4.5% by weight of thesaline solution. Other formulations comprise liquid or lyophilizedformulation.

The appropriate dosage will, of course, vary depending upon, forexample, the particular IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof) to be employed, the host, the mode ofadministration and the nature and severity of the condition beingtreated, and on the nature of prior treatments that the patient hasundergone. Ultimately, the attending health care provider will decidethe amount of the IL-17 antagonist (e.g., secukinumab) with which totreat each individual subject. In some embodiments, the attending healthcare provider may administer low doses of the IL-17 binding molecule andobserve the subject's response. In other embodiments, the initialdose(s) of IL-17 antagonist (e.g., secukinumab) administered to asubject are high, and then are titrated downward until signs of relapseoccur. Larger doses of the IL-17 antagonist (e.g., secukinumab) may beadministered until the optimal therapeutic effect is obtained for thesubject, and at that point the dosage is not generally increasedfurther.

An IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibodyor antigen binding fragment thereof, e.g., secukinumab) or IL-17receptor binding molecule (e.g., IL-17 antibody or antigen bindingfragment thereof) is conveniently administered parenterally,intravenously, e.g. into the antecubital or other peripheral vein,intramuscularly, or subcutaneously. The duration of intravenous (i.v.)therapy using a pharmaceutical composition of the present disclosurewill vary, depending on the severity of the disease being treated andthe condition and personal response of each individual patient. Alsocontemplated is subcutaneous (s.c.) therapy using a pharmaceuticalcomposition of the present disclosure. The health care provider willdecide on the appropriate duration of i.v. or s.c. therapy and thetiming of administration of the therapy, using the pharmaceuticalcomposition of the present disclosure.

Satisfactory results (treatment, prophylaxis, delay of onset ofsymptoms) are generally indicated to be obtained at dosages from about0.05 mg to about 30 mg per kilogram body weight, more usually from about0.1 mg to about 20 mg per kilogram body weight. The frequency of dosingmay be in the range from about once per day up to about once every threemonths, e.g., in the range from about once every 2 weeks up to aboutonce every 12 weeks, e.g., once every four to eight weeks. The dosingfrequency will depend on, inter alia, the phase of the treatmentregimen.

The use of antibodies as the active ingredient of pharmaceuticals is nowwidespread, including the products HERCEPTIN™ (trastuzumab), RITUXAN™(rituximab), SYNAGIS™ (palivizumab), etc. Techniques for purification ofantibodies to a pharmaceutical grade are well known in the art.Antibodies, e.g., antibodies to IL-17, are typically formulated eitherin aqueous form ready for parenteral administration or as lyophilisatesfor reconstitution with a suitable diluent prior to administration. Insome embodiments of the disclosed methods and uses, the IL-17antagonist, e.g., IL-17 antibody, e.g., secukinumab, is formulated as alyophilisate. Suitable lyophilisate formulations can be reconstituted ina small liquid volume (e.g., 2 ml or less) to allow subcutaneousadministration and can provide solutions with low levels of antibodyaggregation. The composition will usually be sterile, at least at thetime of its formation. The composition will usually be non pyrogenice.g. containing <1 EU (endotoxin unit, a standard measure) per dose, andpreferably <0.1 EU per dose. The composition is preferably gluten free.Within formulations disclosed herein, antibodies preferably makes up atleast 80% by weight (e.g. at least 90%, 95%, 97%, 98%, 99% or more) ofthe total protein in the formulation. The antibody is thus in purifiedform.

Lyophilisates

Techniques for lyophilisation of antibodies are well known in the art,e.g., see Rey & May (2004) Freeze-Drying/Lyophilization OfPharmaceutical & Biological Products ISBN 0824748689, WO92/15331, USpatent application 2008/0286280, WO03/041637, WO2008/116103,WO2008/029908, WO2007/074880, WO03/009817, and WO98/022136. For example,antibody products SYNAGIS™, REMICADE™, RAPTIVA™, SIMULECT™, XOLAIR™ andHERCEPTIN™ are supplied as lyophilisates. These antibodies arereconstituted to various final concentrations, e.g. SIMULECT™, isreconstituted to a concentration of 4 mg/ml antibody, REMICADE™ isreconstituted to a concentration of 10 mg/ml, HERCEPTIN™ to 21 mg/ml,SYNAGIS™ and RAPTIVA™ to 100 mg/ml, and XOLAIR™ to 125 mg/ml.

Lyophilisates of the disclosure can be reconstituted to give aqueouscompositions with an anti-IL-17 antibody concentration of at least about15 mg/ml. The antibody concentration can be much higher than about 15mg/ml, e.g., >about 15 mg/ml, >about 20 mg/ml, >about 25 mg/ml, >about50 mg/ml, >about 75 mg/ml, >about 100 mg/ml, >about 125 mg/ml, >about150 mg/ml, >about 300 mg/ml or higher.

The lyophilisate may include, in addition to the anti-IL-17 antibody,further components such as one or more of the following: (i) a sugar;(ii) a buffering agent; (iii) a surfactant; and (iv) a stabilizingagent. Inclusion of each of such additional components (i), (ii) and(iii) is typical, and can give compositions with low aggregation of theanti-IL-17 antibody. Inclusion of component (iv) is advantageous becauseit has been shown to further reduce aggregation after storage.

When present, components (i) to (iv) will be at a pre-lyophilisationconcentration sufficient to maintain the anti-IL-17 antibody in a formwhich is active and soluble after storage (under normal conditions) andreconstitution. The components will also be present afterreconstitution.

Suitable sugars for use with the invention include, but are not limitedto, monosaccharides, disaccharides and trisaccharides. For example, thesugar may be sucrose, trehalose, raffinose, maltose, sorbitol ormannitol. The sugar may be a sugar alcohol or an amino sugar. Sucroseand trehalose (e.g., at a concentration of about 175 mM to about 300 mM,e.g., about 175 mM, about 180 mM, about 185 mM, about 190 mM, about 195mM, about 200 mM, about 225 mM, about 250 mM, about 275 mM, about 300mM) are particularly useful.

Suitable buffering agents for use with the invention include, but arenot limited to, a histidine buffer, a citrate buffer, a phosphatebuffer, a succinate buffer, an acetate buffer, or a Tris buffer. Ahistidine buffer (e.g., at a concentration of about 5 mM to about 50 mM,e.g., about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM,about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM) isparticularly useful.

Suitable surfactants for use with the invention include, but are notlimited to, non ionic surfactants, ionic surfactants and zwitterionicsurfactants. Typical surfactants for use with the invention include, butare not limited to, sorbitan fatty acid esters (e.g., sorbitanmonocaprylate, sorbitan monolaurate, sorbitan monopalmitate), sorbitantrioleate, glycerine fatty acid esters (e.g., glycerine monocaprylate,glycerine monomyristate, glycerine monostearate), polyglycerine fattyacid esters (e.g., decaglyceryl monostearate, decaglyceryl distearate,decaglyceryl monolinoleate), polyoxyethylene sorbitan fatty acid esters(e.g., polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitanmonooleate, polyoxyethylene sorbitan monostearate, polyoxyethylenesorbitan monopalmitate, polyoxyethylene sorbitan trioleate,polyoxyethylene sorbitan tristearate), polyoxyethylene sorbitol fattyacid esters (e.g., polyoxyethylene sorbitol tetrastearate,polyoxyethylene sorbitol tetraoleate), polyoxyethylene glycerine fattyacid esters (e.g., polyoxyethylene glyceryl monostearate), polyethyleneglycol fatty acid esters (e.g., polyethylene glycol distearate),polyoxyethylene alkyl ethers (e.g., polyoxyethylene lauryl ether),polyoxyethylene polyoxypropylene alkyl ethers (e.g., polyoxyethylenepolyoxypropylene glycol, polyoxyethylene polyoxypropylene propyl ether,polyoxyethylene polyoxypropylene cetyl ether), polyoxyethylenealkylphenyl ethers (e.g., polyoxyethylene nonylphenyl ether),polyoxyethylene hydrogenated castor oils (e.g. polyoxyethylene castoroil, polyoxyethylene hydrogenated castor oil), polyoxyethylene beeswaxderivatives (e.g., polyoxyethylene sorbitol beeswax), polyoxyethylenelanolin derivatives (e.g., polyoxyethylene lanolin), and polyoxyethylenefatty acid amides (e.g., polyoxyethylene stearic acid amide); C10-C18alkyl sulfates (e.g., sodium cetyl sulfate, sodium lauryl sulfate,sodium oleyl sulfate), polyoxyethylene C10-C18 alkyl ether sulfate withan average of 2 to 4 moles of ethylene oxide units added (e.g., sodiumpolyoxyethylene lauryl sulfate), and C1-C18 alkyl sulfosuccinate estersalts (e.g., sodium lauryl sulfosuccinate ester); and naturalsurfactants such as lecithin, glycerophospholipid, sphingophospholipids(e.g., sphingomyelin), and sucrose esters of C12-C18 fatty acids. Acomposition may include one or more of these surfactants. Preferredsurfactants are polyoxyethylene sorbitan fatty acid esters e.g.polysorbate 20, 40, 60 or 80. Polysorbate 80 (Tween 80) (e.g., at aconcentration of about 0.01%-about 0.1%, e.g., about 0.02%, about 0.04%,about 0.06%, about 0.08%, about 0.1%) is particularly useful.

A lyophilisate may include active ingredients in addition to theantibody. For instance, further pharmacological agents may be included,such as chemotherapeutic compounds. For instance, methotrexate may beincluded, and it is known to include methotrexate sodium inlyophilisates.

The pH of an aqueous antibody formulation prior to lyophilisation may bein the range 4.0-8.0, which a pH in the range about 5.5-about 7.4 beingtypical, e.g., about 5.5, about 5.6, about 5.7, about 5.8, about 5.9,about 6, about 6.2, about 6.4, about 6.6, about 6.7, about 6.8, about6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4.

Disclosed are antibody lyophilisates comprising about 25 mg, 50 mg, 75mg, 150 mg, or 300 mg of an anti-IL-17 antibody—preferably 75 mg-150 mg(e.g., 75 mg or 150 mg) of an anti-IL-17 antibody. Disclosed are alsolyophilisates comprising: an IL-17 antibody, e.g., secukinumab; a sugar;a buffering agent; and a surfactant. The composition may also include astabilizing agent.

Disclosed are also processes for preparing a lyophilisate, comprisingsteps of: (i) preparing an aqueous solution comprising an IL-17antibody, e.g., secukinumab, a sugar, a buffering agent, a surfactant,and optionally a stabilizing agent; and (ii) lyophilising the aqueoussolution.

Reconstituates

Before a lyophilisate can be administered to a patient it should bereconstituted with a liquid reconstituent (e.g., an aqueous liquid) toprovide a liquid composition (hereinafter a “reconstituate”).

Lyophilisates may be reconstituted with various volumes (e.g., 0.25 ml,0.5 ml, 1.0 ml, 1.5 ml, etc.) of a reconstituent (e.g., an aqueousreconstituent, e.g., water). This step permits antibody and othercomponents in the lyophilisate to re-dissolve to give a solution whichis suitable for injection to a patient. The volume of aqueous materialused for reconstitution dictates the concentration of antibody in aresulting pharmaceutical composition, and may also determine the routeof administration. Reconstitution with a smaller volume of reconstituentthan the pre-lyophilisation volume provides a composition which is moreconcentrated than before lyophilisation. As mentioned above,lyophilisates of the invention can be reconstituted to give aqueouscompositions with an anti-IL-17 antibody concentration of at least about75 mg/ml (or higher), and the volume of reconstituent will be selectedaccordingly.

Disclosed herein are reconstituates comprising an anti-IL-17 antibody,wherein the reconstituate has an antibody concentration of at leastabout 25 mg/ml, 50 mg/ml, 75 mg/ml, 150 mg/ml, or 300 mg/ml—preferably75 mg/ml-150 mg/ml (e.g., 75 mg/ml or 150 mg/ml). Ideally the volume ofthe reconstituate is small, e.g., 0.25-2.0 ml, in order to facilitatesubcutaneous administration of the IL-17 antagonist.

Typical reconstituents for lyophilised antibodies include sterile wateror buffer, optionally containing a preservative. If the lyophilisateincludes a buffering agent, then the reconstituent may include furtherbuffering agent (which may be the same as or different from thelyophilisate's buffering agent) or it may instead include no bufferingagent (e.g. WFI, physiological saline). A reconstituate may includepharmacological agents, such as chemotherapeutic compounds, facilitatingco delivery together with the antibody.

When present, components (i) to (iv) mentioned above will be at aconcentration sufficient to maintain the anti-IL-17 antibody in activesoluble form, after reconstitution, under normal storage conditionswhile retaining pharmaceutical acceptability at the point of use.

In addition to antibody and water, reconstituates may include furthercomponents, derived from the lyophilisate and/or the reconstituent. Suchcomponents include, but are not limited to, buffers, salts, stabilizingagents, glycerol, alcohols, preservatives, surfactants, etc. A thoroughdiscussion of such pharmaceutical ingredients is available in Gennaro(2000) Remington: The Science and Practice of Pharmacy. 20th edition,ISBN: 0683306472.

Disclosed are reconstituate pharmaceutical compositions comprising: anIL-17 antibody, e.g., secukinumab; a sugar; a buffering agent; and asurfactant. The composition may also include a stabilizing agent.Disclosed are also processes for preparing a reconstituate, comprisingmixing a lyophilisate with an aqueous reconstituent, wherein thelyophilisate comprises an IL-17 antibody, e.g., secukinumab, a sugar, abuffering agent, a surfactant, and optionally a stabilizing agent.

Disclosed herein are methods of treating rheumatoid arthritis (RA),comprising administering a therapeutically effective amount of an IL-17antagonist to a high risk RA patient.

Disclosed herein are also methods of treating rheumatoid arthritis (RA),comprising: a) selecting a patient for treatment on the basis of thepatient being a high risk RA patient; and b) administering atherapeutically effective amount of an IL-17 antagonist to the patient.

Disclosed herein are methods of treating rheumatoid arthritis (RA),comprising: a) assaying a sample from a patient for: i. rheumatoidfactor (RF), anti-citrullinated protein antibody (ACPA), or RF and ACPA;and ii. C-reactive protein (CRP), an erythrocyte sedimentation rate(ESR), or both CRP and an ESR; and b) thereafter, administering thepatient an IL-17 antagonist to the patient if the patient is RF+, ACPA+,or RF+ and ACPA+ and the patient has a high level of CRP, a high ESR, ora high level of CRP and a high ESR.

Disclosed herein are methods of treating rheumatoid arthritis (RA),comprising administering a therapeutically effective amount of an IL-17antagonist to a patient, provided that the patient is selected fortreatment on the basis of: a) being RF+, ACPA+, or both RF+ and ACPA+;and b) having a high level of CRP, a high ESR, or both a high level ofCRP and a high ESR. In some embodiments, the step of administeringcomprises: a) administering the IL-17 antagonist to the patient duringan induction regimen; and b) thereafter administering the IL-17antagonist to the patient during a maintenance regimen.

Disclosed herein are methods of treating rheumatoid arthritis (RA),comprising: a) administering a high risk RA patient three doses of about10 mg/kg of an IL-17 antagonist, each of the three doses being deliveredevery other week; and b) thereafter administering about 75 mg-about 150mg of the IL-17 antagonist to the patient every month, beginning onemonth from delivery of the third intravenous dose.

Disclosed herein are therapeutic regimens for treating rheumatoidarthritis (RA), comprising: a) selecting a patient having RA based onthe following criteria; i. the patient is RF+, ACPA+, or both RF+ andACPA+; and ii. the patient has a high level of CRP, a high ESR, or botha high level of CRP and a high ESR; and b) administering the patientthree doses of about 10 mg/kg of an IL-17 antagonist, the first dosebeing delivered during week zero, the second dose being delivered duringweek two, and the third dose being delivered during week four; and c)thereafter administering the patient about 75 mg-about 150 mg of theIL-17 antagonist twice a month, monthly, every two months or every threemonths, beginning during week eight.

Disclosed herein are IL-17 antagonists for use in treating rheumatoidarthritis (RA), characterized in that the IL-17 antagonist is to beadministered to a high risk RA patient. Disclosed herein are IL-17antagonists for use in treating rheumatoid arthritis (RA), characterizedin that the IL-17 antagonist is to be administered to a patient selectedfor treatment on the basis of the patient being a high risk RA patient.

Disclosed herein are IL-17 antagonists for use in treating a high riskRA patient. In some embodiments, the high risk RA patient: a) isseropositive for rheumatoid factor (RF+), anti-citrullinated proteinantibody (ACPA+), or both RF+ and ACPA+; and b) has a high level ofC-reactive protein (CRP), a high erythrocyte sedimentation rate (ESR),or both a high level of CRP and a high ESR. In some embodiments, a highlevel of CRP is ≥10 mg/L, as measured by hsCRP. In some embodiments, ahigh ESR is ≥28 mm/h.

Disclosed herein are IL-17 antagonists for use in treating rheumatoidarthritis (RA), characterized in that the IL-17 antagonist is to beadministered to a patient, provided that the patient is selected fortreatment on the basis of: a) being RF+, ACPA+, or both RF+ and ACPA+;and b) having a high level of CRP, a high ESR, or both a high level ofCRP and a high ESR.

Disclosed herein are IL-17 antagonists for use in treating rheumatoidarthritis (RA), characterized in that the IL-17 antagonist is to be: a)administered to a high risk RA patient as three doses of about 10 mg/kg,each of the three doses being delivered every other week; and b)thereafter administered to the patient as a dose of about 75 mg-about150 mg every month, beginning one month from delivery of the thirdintravenous dose.

Disclosed herein are IL-17 antagonists for use in treating rheumatoidarthritis (RA), characterized in that: a) a sample from a patient isassayed for: i. rheumatoid factor (RF), anti-citrullinated proteinantibody (ACPA), or RF and ACPA; and ii.C-reactive protein (CRP), anerythrocyte sedimentation rate (ESR), or both CRP and an ESR; and b) theIL-17 antagonist is administered to the patient if the patient is RF+,ACPA+, or RF+ and ACPA+ and the patient has a high level of CRP, a highESR, or a high level of CRP and a high ESR.

Disclosed herein are uses of an IL-17 antagonist for the manufacture ofa medicament for treating RA, characterized in that the IL-17 antagonistis to be administered to high risk RA patient.

Disclosed herein are uses of an IL-17 antagonist for the manufacture ofa medicament for treating RA, characterized in that the IL-17 antagonistis to be administered to high risk RA patient during an inductionregimen followed by a maintenance regimen.

Disclosed herein are pharmaceutical composition for treating RA,comprising as an active ingredient an IL-17 antagonist, wherein theIL-17 antagonist is to be administered to a high risk RA patient.

Disclosed herein are pharmaceutical composition for treating RA,comprising as an active ingredient an IL-17 antagonist, wherein theIL-17 antagonist is to be administered to a high risk RA patient duringan induction regimen followed by a maintenance regimen.

Disclosed herein are therapeutic regimens for treating RA, comprising:a) selecting a high risk RA patient; b) administering about 10 mg/kg ofan IL-17 antagonist to the patient during weeks 0, 2 and 4; and c)thereafter administering about 75 mg-about 150 mg of the IL-17antagonist to the patient monthly, beginning week 8.

Disclosed herein are methods of treating a RA patient or a high risk RApatient, comprising: a) administering an IL-17 binding molecule to apatient in need thereof during an induction regimen that provides a meanmaximum plasma concentration (C_(max)) of the IL-17 binding molecule ofabout 360 μg/ml; and b) thereafter administering the IL-17 bindingmolecule to the patient during a maintenance regimen that provides: i)an average steady-state trough level of the IL-17 binding moleculebetween about 8 μg/ml-about 30 μg/ml; and/or ii) a mean AUC tau atsteady state of about 331 mg*day/L-about 1323 mg*day/L.

Disclosed herein are IL-17 binding molecules for use in treating a RApatient or a high risk RA patient, characterized in that the IL-17binding molecule: a) is to be administered to the patient during aninduction regimen that provides a mean maximum plasma concentration(C_(max)) of the IL-17 binding molecule of about 360 μg/ml; and b)thereafter, is to be administered to the patient during a maintenanceregimen that provides: i) an average steady-state trough level of theIL-17 binding molecule between about 8 μg/ml-about 30 μg/ml; and/or ii)a mean AUC tau at steady state of about 331 mg*day/L-about 1323mg*day/L.

Disclosed herein are methods of treating a high risk RA patient,comprising: a) administering an IL-17 binding molecule to a patient inneed thereof during an induction regimen that provides a mean maximumplasma concentration (C_(max)) of the IL-17 binding molecule of about401 μg/ml; and b) thereafter administering the IL-17 binding molecule tothe patient during a maintenance regimen that provides: i) an averagesteady-state trough level of the IL-17 binding molecule of about 9.4μg/ml-about 31 μg/ml; and/or ii) a mean AUC tau at steady state of about314 mg*day/L-about 1256 mg*day/L.

Disclosed herein are IL-17 binding molecule for use in treatingpsoriasis, characterized in that the IL-17 binding molecule: a) is to beadministered to the patient during an induction regimen that provides amean maximum plasma concentration (C_(max)) of the IL-17 bindingmolecule of about 401 μg/ml; and b) thereafter, is to be administered tothe patient during a maintenance regimen that provides: i) an averagesteady-state trough level of the IL-17 binding molecule of about 9.4μg/ml-about 31 μg/ml; and/or ii) a mean AUC tau at steady state of about314 mg*day/L-about 1256 mg*day/L.

In some embodiments, the maintenance regimen provides an averagesteady-state trough level of the IL-17 binding molecule of about 9.4μg/ml-about 17.3 μg/ml. In some embodiments, the maintenance provides anaverage steady-state trough level of the IL-17 binding molecule of about9.4 μg/ml or about 17.3 μg/ml. In some embodiments, the inductionregimen comprises intravenous administration of the IL-17 bindingmolecule every other week. In some embodiments, the maintenance regimencomprises monthly subcutaneous administration of the IL-17 bindingmolecule.

Disclosed herein are IL-17 antagonists in preparation of a medicamentfor the treatment of RA, provided that the patient is selected for thetreatment on the basis of: a) being RF+, ACPA+, or both RF+ and ACPA+;and b) having a high level of CRP, a high ESR, or both a high level ofCRP and a high ESR.

Disclosed herein are IL-17 antagonists for the manufacture of amedicament for the treatment of RA in a patient characterized as: a)being RF+, ACPA+, or both RF+ and ACPA+; and b) having a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR, wherein themedicament is formulated to comprise containers, each container having asufficient amount of the IL-17 antagonist to allow delivery of at leastabout 75 mg-about 150 mg IL-17 antagonist per unit dose.

Disclosed herein are IL-17 antagonists for the manufacture of amedicament for the treatment of RA in a patient characterized as: a)being RF+, ACPA+, or both RF+ and ACPA+; and b) having a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR, wherein themedicament is formulated to comprise containers, each container having asufficient amount of the IL-17 antagonist to allow delivery of at leastabout 10 mg/kg per unit dose.

Disclosed herein are IL-17 antagonists for the manufacture of amedicament for the treatment of RA in a patient characterized as: a)being RF+, ACPA+, or both RF+ and ACPA+; and b) having a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR, wherein themedicament is formulated at a dosage to allow intravenous delivery ofabout 10 mg/kg per unit dose.

Disclosed herein are IL-17 antagonists for the manufacture of amedicament for the treatment of RA in a patient characterized as: a)being RF+, ACPA+, or both RF+ and ACPA+; and b) having a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR, wherein themedicament is formulated at a dosage to allow subcutaneous delivery ofabout 75 mg-about 150 mg IL-17 antagonist per unit dose.

Disclosed herein are in vitro test methods for selecting a patient fortreatment of RA, comprising determining if: i. the patient is RF+,ACPA+, or both RF+ and ACPA+; and ii. the patient has a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR. In someembodiments of the disclosed in vitro test methods, the patient has animproved therapeutic response to the following regimen: a) administeringthe patient three doses of about 10 mg/kg of an IL-17 antagonist, thefirst dose being delivered during week zero, the second dose beingdelivered during week two, and the third dose being delivered duringweek four; and a) thereafter administering the patient about 75 mg-about150 mg of the IL-17 antagonist twice a month, monthly, every two monthsor every three months, beginning during week eight.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the high risk RA patient: a) is seropositivefor rheumatoid factor (RF+), anti-citrullinated protein antibody(ACPA+), or both RF+ and ACPA+; and b) has a high level of C-reactiveprotein (CRP), a high erythrocyte sedimentation rate (ESR), or both ahigh level of CRP and a high ESR. In some embodiments, the high level ofCRP is ≥10 mg/L, as measured by hsCRP. In some embodiments, the high ESRis ≥28 mm/h.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the step of administering comprisesintravenously administering three doses of about 10 mg/kg of the IL-17antagonist to said patient, each of said doses being administered everyother week. In some embodiments, the step of administering comprisessubcutaneously administering doses of about 75 mg-about 150 mg of theIL-17 antagonist to said patient, each of said doses being administeredmonthly. In some embodiments, the step of administering comprises: a)administering the IL-17 antagonist to the high risk RA patient during aninduction regimen; and b) thereafter administering the IL-17 antagonistto the patient during a maintenance regimen.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the induction regimen comprisesadministering the patient three doses of about 10 mg/kg of the IL-17antagonist. In some embodiments, the first dose of about 10 mg/kg isdelivered during week zero, the second dose of about 10 mg/kg isdelivered during week two, and the third dose of about 10 mg/kg isdelivered during week four.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the maintenance regimen comprisesadministering the patient about 75 mg-about 300 mg of the IL-17antagonist. In some embodiments, the maintenance regimen comprisessubcutaneously administering the patient about 75 mg-about 300 mg of theIL-17 antagonist twice a month, monthly, every two months or every threemonths. In some embodiments, the maintenance regimen comprisessubcutaneously administering the patient about 75 mg-about 150 mg of theIL-17 antagonist twice a month, monthly, every two months or every threemonths, beginning during week eight. In some embodiments, themaintenance regimen comprises subcutaneously administering the patientabout 75 mg or about 150 mg of the IL-17 antagonist monthly, beginningduring week eight.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, prior to administering the IL-17 antagonistthe patient had a previous RA treatment comprising administering atleast one anti-rheumatic agent selected from the group consisting of animmunosuppressive agent, a disease-modifying anti-rheumatic drug(DMARD), a pain-control drug, a steroid, a non-steroidalanti-inflammatory drug (NSAID), a cytokine antagonist, a bone anabolic,a bone anti-resorptive, and combinations thereof. In some embodiments,the prior to administering the IL-17 antagonist the patient had aninadequate response to, had failure to or was intolerant to treatmentwith a DMARD, a TNF alpha antagonist, or methotrexate.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the patient is additionally administered atherapeutically effective amount of at least one anti-rheumatic agentselected from the group consisting of an immunosuppressive agent, aDMARD, a pain-control drug, a steroid, a NSAID, a cytokine antagonist, abone anabolic, a bone anti-resorptive, and combinations thereof.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the IL-17 antagonist is administered asthree doses of about 10 mg/kg, each of said doses being administeredevery other week. In some embodiments, the IL-17 antagonist isadministered as doses of about 75 mg-about 300 mg, each of said dosesbeing administered monthly.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the IL-17 antagonist is to be administeredto the patient during an induction regimen and thereafter administeredto the patient during a maintenance regimen. In some embodiments, theinduction regimen comprises administering the patient three doses ofabout 10 mg/kg of the IL-17 antagonist. In some embodiments, the firstdose of about 10 mg/kg is delivered during week zero, the second dose ofabout 10 mg/kg is delivered during week two, and the third dose of about10 mg/kg is delivered during week four.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the maintenance regimen comprisesadministering the patient about 75 mg-about 300 mg of the IL-17antagonist. In some embodiments, the maintenance regimen comprisessubcutaneously administering the patient about 75 mg-about 300 mg of theIL-17 antagonist twice a month, monthly, every two months or every threemonths. In some embodiments, the maintenance regimen comprisessubcutaneously administering the patient about 75 mg-about 150 mg of theIL-17 antagonist twice a month, monthly, every two months or every threemonths, beginning during week eight. In some embodiments, themaintenance regimen comprises subcutaneously administering the patientabout 75 mg or about 150 mg of the IL-17 antagonist monthly, beginningduring week eight.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the high risk RA patient: a) is seropositivefor rheumatoid factor (RF+), anti-citrullinated protein antibody(ACPA+), or both RF+ and ACPA+; and b) has a high level of C-reactiveprotein (CRP), a high erythrocyte sedimentation rate (ESR), or both ahigh level of CRP and a high ESR.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the induction regimen maintains the troughlevel of the IL-17 binding molecule above 80 μg/ml for a 10 week period.In some embodiments, the maintenance regimen provides an averagesteady-state trough level of the IL-17 binding molecule of about 8μg/ml-about 17 μg/ml. In some embodiments, the maintenance provides anaverage steady-state trough level of the IL-17 binding molecule of about8 μg/ml or about 17 μg/ml.

In some embodiments of the disclosed methods, kits, uses, pharmaceuticalcompositions, and regimens, the IL-17 antagonist is an IL-17 bindingmolecule or an IL-17 receptor binding molecule. In some embodiments, theIL-17 binding molecule or an IL-17 receptor binding molecule is an IL-17binding molecule (e.g., IL-17 antibody) selected from the groupconsisting of: a) secukinumab; b) an IL-17 antibody that binds to anepitope of IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Val124,Thr125, Pro126, Ile127, Val128, His129; c) an IL-17 antibody that bindsto an epitope of IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80; d)an IL-17 antibody that binds to an epitope of an IL-17 homodimer havingtwo mature IL-17 protein chains, said epitope comprising Leu74, Tyr85,His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 onone chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain; e)an IL-17 antibody that binds to an epitope of an IL-17 homodimer havingtwo mature IL-17 protein chains, said epitope comprising Leu74, Tyr85,His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 onone chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain,wherein the IL-17 binding molecule has a K_(D) of about 100-200 pM, andwherein the IL-17 binding molecule has an in vivo half-life of about 4weeks; and f) an IL-17 antibody that comprises an antibody selected fromthe group consisting of: i) an immunoglobulin heavy chain variabledomain (V_(H)) comprising the amino acid sequence set forth as SEQ IDNO:8; ii) an immunoglobulin light chain variable domain (V_(L))comprising the amino acid sequence set forth as SEQ ID NO:10; iii) animmunoglobulin V_(H) domain comprising the amino acid sequence set forthas SEQ ID NO:8 and an immunoglobulin V_(L) domain comprising the aminoacid sequence set forth as SEQ ID NO:10; iv) an immunoglobulin V_(H)domain comprising the hypervariable regions set forth as SEQ ID NO:1,SEQ ID NO:2, and SEQ ID NO:3; v) an immunoglobulin V_(L) domaincomprising the hypervariable regions set forth as SEQ ID NO:4, SEQ IDNO:5 and SEQ ID NO:6; vi) an immunoglobulin V_(H) domain comprising thehypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ IDNO:13; vii) an immunoglobulin V_(H) domain comprising the hypervariableregions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 and animmunoglobulin V_(L) domain comprising the hypervariable regions setforth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; and viii) animmunoglobulin V_(H) domain comprising the hypervariable regions setforth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 and animmunoglobulin V_(L) domain comprising the hypervariable regions setforth as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.

In preferred embodiments of the disclosed methods, kits, uses,pharmaceutical compositions, and regimens, the IL-17 binding molecule isa human antibody. In even more preferred embodiments of the disclosedmethods, kits, uses, pharmaceutical compositions, and regimens, theIL-17 binding molecule is secukinumab.

As used herein, the phrase “container having a sufficient amount of theIL-17 antagonist to allow delivery of [a designated dose]” is used tomean that a given container (e.g., vial, pen, syringe) has disposedtherein a volume of an IL-17 antagonist (e.g., as part of apharmaceutical composition) that can be used to provide a desired dose.As an example, if a desired dose is 75 mg, then a clinician may use 2 mlfrom a container that contains an IL-17 antibody formulation with aconcentration of 37.5 mg/ml, 1 ml from a container that contains anIL-17 antibody formulation with a concentration of 75 mg/ml, 0.5 ml froma container contains an IL-17 antibody formulation with a concentrationof 150 mg/ml, etc. In each such case, these containers have a sufficientamount of the IL-17 antagonist to allow delivery of the desired 75 mgdose.

As used herein, the phrase “formulated at a dosage to allow [route ofadministration] delivery of [a designated dose]” is used to mean that agiven pharmaceutical composition can be used to provide a desired doseof an IL-17 antagonist, e.g., an IL-17 antibody, e.g., secukinumab, viaa designated route of administration (e.g., s.c. or i.v.). As anexample, if a desired subcutaneous dose is 75 mg, then a clinician mayuse 2 ml of an IL-17 antibody formulation having a concentration of 37.5mg/ml, 1 ml of an IL-17 antibody formulation having a concentration of75 mg/ml, 0.5 ml of an IL-17 antibody formulation having a concentrationof 150 mg/ml, etc. In each such case, these IL-17 antibody formulationsare at a concentration high enough to allow subcutaneous delivery of theIL-17 antibody. Subcutaneous delivery typically requires delivery ofvolumes of less than about 2 ml, preferably a volume of about 1 ml orless.

In some embodiments, the induction regimen comprises administration of1, 2, 3, 4, 5, 6, or more i.v. doses of the IL-17 antagonist (e.g.,secukinumab), e.g., secukinumab, preferably one, two or three (mostpreferably three) doses of secukinumab delivered every week, every otherweek, every three weeks or every four weeks (monthly). In someembodiments, the induction regimen comprises administration of 10 mg/kgi.v. of the IL-17 antagonist (e.g., secukinumab), e.g., secukinumab.

In some embodiments, induction doses of the IL-17 antagonist (e.g.,secukinumab) may be administered as three i.v. infusions (e.g., 10mg/kg) every other week, i.e., during week zero (e.g., day 1), duringweek two (e.g., about day 15), and during week four (e.g., about day29). In some embodiments, induction doses may be administered as threei.v. infusions (e.g., 10 mg/kg) every three weeks, i.e., during weekzero (e.g., about day 1), during week three (e.g., about day 22), andduring week six (e.g., about day 43). In some embodiments, inductiondoses may be administered as three i.v. infusions (e.g., 10 mg/kg) everyfour weeks (monthly), i.e., during week zero (e.g., about day 1), duringweek four (e.g., about day 29), and during week eight (e.g., about day57).

In some embodiments, induction doses of the IL-17 antagonist (e.g.,secukinumab) may be administered as two i.v. infusions (e.g., 10 mg/kg)every other week, i.e., during week zero (about day 1), and during weektwo (e.g., about day 15). In some embodiments, induction doses may beadministered as two i.v. infusions (e.g., 10 mg/kg) every three weeks,i.e., during week zero (e.g., about day 1) and during week three (e.g.,about day 22). In some embodiments, induction doses may be administeredas two i.v. infusions (e.g., 10 mg/kg) every four weeks (monthly), i.e.,during week zero (e.g., about day 1) and during week four (e.g., aboutday 29).

In some embodiments, induction doses of the IL-17 antagonist (e.g.,secukinumab) may be administered as a single high dose infusion, e.g.,30 mg/kg.

In further embodiments, the induction regimen comprises administrationof 1, 2, 3, 4, 5, 6, or more daily or weekly s.c. doses of the IL-17antagonist (e.g., secukinumab), preferably three to five (e.g., four)weekly doses of secukinumab. In some embodiments, the induction dosagethat may be administered daily or weekly is about 75 mg-about 300 mg ofthe IL-17 antagonist (e.g., secukinumab) delivered s.c. (e.g, about 75mg-about 150 mg, e.g., about 75 mg or about 150 mg).

In some embodiments, the induction regimen comprises administration ofdaily s.c. doses of the IL-17 antagonist (e.g., secukinumab), e.g.,daily s.c. doses of secukinumab (e.g., about 75 mg-about 300 mg, e.g,about 75 mg-about 150 mg, e.g., about 75 mg or about 150 mg), deliveredon days 1-7. In some embodiments, the induction regimen comprisesadministration of weekly s.c. doses of the IL-17 antagonist (e.g.,secukinumab), e.g., weekly s.c. doses of secukinumab, delivered duringweek zero, one, two, and three.

In other embodiments, the dose(s) secukinumab administered to a subjectmay be higher and more frequent (i.e., weekly for the first month oftreatment) during an induction regimen, and then the patient may bemaintained at a lower dose.

In some embodiments, the maintenance regimen comprises subcutaneouslyadministering the patient about 75 mg or about 150 mg of the IL-17binding molecule if the patient weighs less than 90 kg. In someembodiments, the maintenance regimen comprises subcutaneouslyadministering the patient about 150 mg or about 300 mg of the IL-17binding molecule if the patient weighs more than or equal to 90 kg.

For a maintenance regimen, a dose of the IL-17 antagonist (e.g.,secukinumab) may be provided twice a month (i.e., every two weeks,bimonthly or every other week, i.e., about every 14 days), every month(i.e., every 4 weeks, i.e., about every 28 days), every two months(i.e., every other month or every 8 weeks, i.e., about every 56 days),or every three months (i.e., every 12 weeks, i.e., about every 84 days).As used herein, the date of the first dose of a maintenance regimen willbe measured from the final dose of the induction regimen. Thus, as anexample, if the final dose of the induction regimen is provided duringweek four, then a first dose as part of a bimonthly maintenance regimenmay be delivered during week six (about day 43), a first dose as part ofa monthly maintenance regimen may be delivered during week eight (aboutday 57), a first dose as part of an every two month maintenance regimenmay be delivered during week twelve (about 85 days), a first dose aspart of an every three month maintenance regimen may be delivered duringweek sixteen (about 113 days), etc. In some embodiments, the first doseof the maintenance regimen is delivered every month (monthly, aboutevery four weeks), beginning one month (i.e., about four weeks) fromdelivery of a final induction (e.g., s.c. or i.v. induction) dose. Insome embodiments, the first dose of the maintenance regimen is deliveredevery month (monthly, about every four weeks), beginning one month(i.e., about four weeks) from delivery of a third i.v. induction dose.

In some embodiments, the maintenance regimen comprises administration ofthe IL-17 antagonist (e.g., secukinumab), e.g., about 75 mg-about 300 mg(e.g, about 75 mg-about 150 mg, e.g., about 75 mg or about 150 mg)delivered bimonthly, monthly, every two months or every three months. Insome embodiments, the IL-17 antagonist (e.g., secukinumab) is delivereds.c. during the maintenance regimen. In a preferred embodiment, amaintenance dose is delivered monthly. In some embodiments, a firstmaintenance dose is delivered during week six (e.g., about day 43),seven (e.g., about day 50), eight (e.g., about day 57), nine (e.g.,about day 64), ten (e.g., about day 71), eleven (e.g., about day 78),twelve (e.g., about day 85), or thirteen (e.g., about day 92) of thetreatment regimen, and then monthly (e.g., about every 4 weeks or aboutevery 28 days) thereafter. In some embodiments, the maintenance regimencomprises subcutaneously administering the patient about 75 mg-about 300mg (e.g, about 75 mg-about 150 mg, e.g., about 75 mg or about 150 mg) ofthe IL-17 antagonist (e.g., secukinumab) twice a month, monthly, everytwo months or every three months, beginning during week four, five, six,seven, eight, nine, ten, eleven, or twelve, preferably during weekeight.

Preferred treatment regimens for treating RA patients (e.g., high riskRA patients) and patients having other inflammatory arthritis, e.g.,spondyloarthropathy, ankylosing spondylitis (AS), and psoriaticarthritis (PsA), are provided in Table 5:

TABLE 5 Preferred dosing regimens for treating RA patients(e.g., high risk RA patients) and patients having otherinflammatory arthritis, e.g., spondyloarthropathy,ankylosing spondylitis, and psoriatic arthritis. i.v. induction regimen(3 × 10 every other week) maintenance regimen (150 or 300 mg)first dose = during week 0 first monthly dose = during week 8second dose = during week 2 every month (about 4 weeks) thereafter.third dose = during week 4 i.v. induction regimen(3 × 10 every three weeks) maintenance regimenfirst dose = during week 0 first monthly dose = during week 10second dose = during week 3 every month (about 4 weeks) thereafterthird dose = during week 6 i.v. induction regimen (3 × 10 every month)maintenance regimen first dose = during week 0first monthly dose = during week 12 second dose = during week 4every month (about 4 weeks) thereafter third dose = during week 8i.v. induction regimen  (2 × 10 every other week) maintenance regimenfirst dose = during week 0 first monthly dose = during week 6second dose = during week 2 every month (about 4 weeks) thereafteri.v. induction regimen (2 × 10 every three week) maintenance regimenfirst dose = during week 0 first monthly dose = during week 7second dose = during week 3 every month (about 4 weeks) thereafteri.v. induction regimen (2 × 10 every month) maintenance regimenfirst dose = during week 0 first monthly dose = during week 8second dose = during week every month (about 4 weeks) thereafter.S.C. induction regimen (150 or 300 mg weekly for 4 doses)maintenance regimen first weekly dose = during week 0first monthly dose = during week 7 second weekly dose = during week 1every month (about 4 weeks) thereafter third weekly dose = during week 2fourth weekly dose = during week 3 S.C. induction regimen(150 or 300 mg daily) maintenance regimen dose 1-7 = day 1-7first monthly dose = during week 4 or 5every month (about 4 weeks) thereafter S.C. induction regimen(150 or 300 mg weekly for 5 doses) maintenance regimenfirst weekly dose = during week 0 first monthly dose = during week 8second weekly dose = during week 1every month (about 4 weeks) thereafter third weekly dose = during week 2fourth weekly dose = during week 3 fifth weekly dose = during week 4

It will be understood that a dose need not be provided at an exact timepoint, e.g., a dose due on day 29 could be provided, e.g., on day 24 today 34.

In some embodiments, the dosage of the IL-17 antagonist (e.g.,secukinumab) used in the disclosed induction and/or maintenance regimens(as the case may be) is based on the patient's weight (e.g., whether apatient is under or over 75 kg, 80 kg, 85 kg, 90 kg, 95 kg, 100 kg, 105kg, etc. can be used to define a dosage of the IL-17 antagonist, e.g.,secukinumab, for delivery to the patient). In one embodiment, thepatient is administered about 75 mg or about 150 mg (e.g., delivereds.c.). if the patient weighs less than or equal to about 80 kg. In oneembodiment, the patient is administered about 75 mg or about 150 mg(e.g., delivered s.c.). if the patient weighs less than or equal toabout 90 kg. In one embodiment, the patient is administered about 75 mgor about 150 mg (e.g., delivered s.c.) if the patient weighs less thanor equal to about 100 kg. In another embodiment, the patient isadministered about 150 mg or about 300 mg (e.g., delivered s.c.) if thepatient weighs more than about 80 kg. In another embodiment, the patientis administered about 150 mg or about 300 mg (e.g., delivered s.c.) ifthe patient weighs more than about 90 kg. In another embodiment, thepatient is administered about 150 mg or about 300 mg (e.g., delivereds.c.) if the patient weighs more than about 100 kg.

It will be understood that dose escalation may be required (e.g., duringthe induction and/or maintenance phase) for certain patients, e.g.,patients that display inadequate response to treatment with the IL-17antagonist (e.g., secukinumab). Thus, s.c. doses of the IL-17 antagonist(e.g., secukinumab) may be greater than about 75 mg to about 300 mgs.c., e.g., about 80 mg, about 100 mg, about 125 mg, about 175 mg, about200 mg, about 250 mg, about 350 mg, about 400 mg, etc.; similarly, i.v.doses may be greater than about 10 mg/kg, e.g., about 11 mg/kg, 12mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, etc. It willalso be understood that dose reduction may also be required (e.g.,during the induction and/or maintenance phase) for certain patients,e.g., patients that display adverse events or an adverse response totreatment with the IL-17 antagonist (e.g., secukinumab). Thus, doses ofthe IL-17 antagonist (e.g., secukinumab) may be less than about 75 mg toabout 300 mg s.c., e.g., about 25 mg, about 50 mg, about 80 mg, about100 mg, about 125 mg, about 175 mg, about 200 mg, 250 mg, etc.;similarly, i.v. doses may be less than about 10 mg/kg, e.g., about 9mg/kg, 8 mg/kg, 5 mg/kg, 4 mg/kg, 3 mg/kg, 2 mg/kg, 1 mg/kg, etc.

In some embodiments of the above methods, uses, pharmaceuticalcompositions, kits and treatment regimens, a CRP level of ≥about 3 mg/L(e.g., 3 mg/L), ≥about 5 mg/L (e.g., 5 mg/L), ≥about 10 mg/L (e.g., 10mg/L), ≥about 15 mg/L (e.g., 15 mg/L) is considered a high level of CRP.In some embodiments, a CRP level of ≥200 nmol/L or ≥240 nmol/L isconsidered a high CRP level. In a preferred embodiment, a CRP level ofgreater than or equal (≥) to about 10 mg/L (e.g., 10 mg/L), e.g., asmeasured by a high sensitivity CRP assay, is considered a high CRPlevel. In some embodiments, a high level of CRP is >about 10mg/L, >about 20 mg/L or >about 30 mg/L.

In some embodiments of the above methods, uses, pharmaceuticalcompositions, kits and treatment regimens, “high ESR” may be determinedbased on the following rule: normal maximum ESR (mm/h)≤(Age (years)+10(if female))/2. As a result, a “high ESR”>(Age (years)+10 (iffemale))/2. In some embodiments, a “high ESR” may be determined based onthe following rule: normal maximum ESR (mm/h)≤(Age (years)+5 (iffemale))/2. As a result, a “high ESR”>(Age (years)+5 (if female))/2. Insome embodiments, an ESR of ≥20 mm/h is a high ESR for females. In someembodiments, an ESR of ≥15 mm/h is a high ESR for males. In a preferredembodiment, an ESR of greater than or equal (≥) to 28 mm/h is a highESR.

In some embodiments of the above methods, uses, pharmaceuticalcompositions, kits and treatment regimens, a patient is RF+ if thepatient's RF value is greater than 20 IU/ml or greater than 30 IU/ml. Insome embodiments, a patient is RF+ if the patient's RF value is greaterthan 40 units/ml or greater than 60 units/ml, as measured by anephelometry test. In some embodiments, a patient is RF+ if thepatient's RF titer is greater than 1:20 or greater than 1:80, asmeasured by a dilution test. In a preferred embodiment, a patient is RF+if the patient's RF value is greater than or equal (≥) to 12 kU/L(kiloUnits/Liter), e.g., as measured by nephelometry.

In some embodiments of the above methods, uses, pharmaceuticalcompositions, kits and treatment regimens, a patient is ACPA+ if thepatient's ACPA value is greater than 1 U/ml, greater than 3 U/ml, orgreater than 5 U/ml, e.g., as determined by an anti-CCP ELISA test. In apreferred embodiment, a patient is ACPA+ if the patient's ACPA value isgreater than 20 units/ml (20 U).

Disclosed herein are also methods of treating rheumatoid arthritis (RA),comprising: a) administering (e.g., subcutaneously administering) a highrisk RA patient four or five doses of about 75 mg-about 300 mg (e.g,about 75 mg-about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof), each of the four or five doses being delivered weekly; and b)thereafter administering about 75 mg-about 300 mg (e.g, about 75mg-about 150 mg, e.g., about 75 mg or about 150 mg) of the IL-17antagonist (e.g., secukinumab) to the patient twice a month, everymonth, every two months or every three months.

Disclosed herein are also therapeutic regimens for treating RA,comprising: a) selecting a patient having rheumatoid arthritis based onthe following criteria; i.) the patient is RF+, ACPA+, or both RF+ andACPA+; and ii.) the patient has a high level of CRP, a high ESR, or botha high level of CRP and a high ESR; and b) administering (e.g.,subcutaneously administering) about 75 mg-about 300 mg (e.g, about 75mg-about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof) to the patient weekly for four or five weeks; and c) thereafteradministering (e.g., subcutaneously administering) about 75 mg-about 300mg (e.g, about 75 mg-about 150 mg, e.g., about 75 mg or about 150 mg) ofthe IL-17 binding molecule to the patient twice a month, every month,every two months or every three months.

Disclosed herein are methods of treating rheumatoid arthritis (RA),comprising administering a therapeutically effective amount of an IL-17antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof) to a RA patient displaying elevated baseline CRP levels (e.g.,greater than about 10 mg/L, greater than about 20 mg/L, greater thanabout 30 mg/L).

Disclosed herein are also therapeutic regimens for treating RA,comprising: a) selecting a patient having rheumatoid arthritis based onthe following criteria: i.) the patient has elevated baseline CRP levels(e.g., greater than about 10 mg/L, greater than about 20 mg/L, greaterthan about 30 mg/L); and b) either i) administering (e.g.,subcutaneously administering) about 75 mg-about 300 mg (e.g, about 75mg-about 150 mg, e.g., about 75 mg or about 150 mg) of an IL-17antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof) to the patient weekly for four or five doses or ii)administering (e.g., i.v. administering) about 10 mg/kg of an IL-17antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab) or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof) to the patient every other week for three doses; and c)thereafter administering (e.g., subcutaneously administering) about 75mg-about 300 mg (e.g, about 75 mg-about 150 mg, e.g., about 75 mg orabout 150 mg) of the IL-17 antagonist (e.g., secukinumab) to the patienttwice a month, every month, every two months or every three months,preferably monthly.

Herein are also provided methods of treating an inflammatory arthritis,comprising an induction regimen, e.g., administering (e.g.,intravenously administering) two or three induction doses of about 10mg/kg of an IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17antibody or antigen binding fragment thereof, e.g., secukinumab) orIL-17 receptor binding molecule (e.g., IL-17 antibody or antigen bindingfragment thereof) (preferably three induction doses) to a patient havingan arthritis, wherein the arthritis is selected from the groupconsisting of rheumatoid arthritis (RA), spondyloarthropathy, ankylosingspondylitis (AS), and psoriatic arthritis (PsA). In some embodiments,the first dose is delivered during week zero, the second dose isdelivered during week two, and the third dose is delivered during weekfour. In some embodiments, the first dose is delivered during week zero,the second dose is delivered during week three, and the third dose isdelivered during week six. In some embodiments, the method furthercomprises a maintenance regimen, e.g., administering (e.g.,subcutaneously administering) about 75 mg-about 300 mg (e.g, about 75mg-about 150 mg, e.g., about 75 mg or about 150 mg) of the IL-17antagonist (e.g., secukinumab) to the patient, wherein the IL-17 bindingmolecule is administered to the patient twice a month, monthly, everytwo months or every three months. In some embodiments the patient is ahigh risk RA patient, e.g., seropositive for rheumatoid factor (RF+),anti-cyclic citrullinated protein antibody (ACPA+), or both RF+ andACPA+; and has a high level of C-reactive protein (CRP), a higherythrocyte sedimentation rate (ESR), or both a high level of CRP and ahigh ESR). In some embodiments, the high level of CRP is ≥10 mg/dL. Insome embodiments, the high ESR is ≥28 mm/h. In further embodiments, theinflammatory arthritis is selected from rheumatoid arthritis (RA),spondyloarthropathy, ankylosing spondylitis, and psoriatic arthritis. Insome embodiment, the patient has RA. In further embodiments, the RApatient is a high risk RA patient. In further embodiments, the high riskRA patient: a) is seropositive for rheumatoid factor (RF+),anti-citrullinated protein antibody (ACPA+), or both RF+ and ACPA+; andb) has a high level of C-reactive protein (CRP), a high erythrocytesedimentation rate (ESR), or both a high level of CRP and a high ESR.

In some embodiments, the IL-17 antagonist, e.g., IL-17 binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof, e.g.,secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof) is used in combination withmethotrexate for the treatment of adult patients with moderately- toseverely-active rheumatoid arthritis who have had an inadequate responseto one or more TNF antagonist therapies. In some embodiments, the IL-17antagonist (e.g., secukinumab) is used alone or in combination withmethotrexate or other disease-modifying anti-rheumatic drugs (DMARDs) toreduce signs and symptoms (e.g., swelling, restricted movement),inducing major clinical response, inhibit the progression of structuraldamage, and improve physical function in adult patients with moderatelyto severely active disease. In some embodiments, the IL-17 antagonist(e.g., secukinumab) is used alone or in combination with methotrexate toreduce signs and symptoms, induce major clinical response, inhibit theprogression of structural damage, and improve physical function inpatients with moderately to severely active rheumatoid arthritis (RA).In some embodiments, the IL-17 antagonist (e.g., secukinumab) is used incombination with methotrexate, for reducing signs and symptoms,inhibiting the progression of structural damage, and improving physicalfunction in patients with moderately to severely active rheumatoidarthritis. In some embodiments, the IL-17 antagonist (e.g., secukinumab)is used for the treatment of adults with moderately to severely activerheumatoid arthritis (RA). In some embodiments, the IL-17 antagonist(e.g., secukinumab) is used for treating moderately to severely activeRheumatoid Arthritis (RA) in adults, in combination with methotrexate.In some embodiments, the IL-17 antagonist (e.g., secukinumab) is usedfor reduction in signs and symptoms and slowing the progression ofstructural damage in moderately to severely active rheumatoid arthritis,in patients who have failed 1 or more disease modifying antirheumaticdrugs (DMARDs). In some embodiments, the IL-17 antagonist (e.g.,secukinumab) is used as a monotherapy or concomitantly withdisease-modifying antirheumatic drugs (DMARDs) for reducing signs andsymptoms, inducing major clinical response, inhibiting the progressionof structural damage, and improving physical function in adult patientswith moderately to severely active rheumatoid arthritis. In someembodiments, the IL-17 antagonist (e.g., secukinumab) is used alone orin combination with methotrexate or other DMARDs to treat adult patientswith moderately to severely active rheumatoid arthritis who have had aninadequate response to one or more TNF antagonist therapies.

Combination Therapies for the Treatment of Arthritis

In practicing the methods of treatment or uses of the presentdisclosure, a therapeutically effective amount of an IL-17 antagonist,e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen bindingfragment thereof, e.g., secukinumab) or IL-17 receptor binding molecule(e.g., IL-17 antibody or antigen binding fragment thereof) isadministered to a subject, e.g., a mammal (e.g., a human). An IL-17binding antagonist (e.g., secukinumab) may be administered in accordancewith the method of the disclosure either alone or in combination withother agents and therapies for treating RA, e.g., in combination with atleast one anti-rheumatic agent, such as an immunosuppressive agent, adisease-modifying anti-rheumatic drug (DMARD), a pain-control drug, asteroid, a non-steroidal anti-inflammatory drug (NSAID), a cytokineantagonist, a bone anabolic, a bone anti-resorptive, and combinationsthereof (e.g., dual and triple therapies). When coadministered with oneor more additional agents, an IL-17 antagonist (e.g., secukinumab) maybe administered either simultaneously with the other agent, orsequentially. If administered sequentially, the attending physician willdecide on the appropriate sequence of administering the IL-17 antagonist(e.g., secukinumab) in combination with other agents.

Non-steroidal anti inflammatory drugs and pain control agents useful incombination with the IL-17 antagonist (e.g., secukinumab) for thetreatment of RA patients, e.g., high risk RA patients, include,propionic acid derivative, acetic acid derivative, enolic acidderivatives, fenamic acid derivatives, Cox inhibitors, e.g.,lumiracoxib, ibuprophen, fenoprofen, ketoprofen, flurbiprofen,oxaprozin, indomethacin, sulindac, etodolac, ketorolac, nabumetone,aspirin, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib,acetominophen, Celecoxib, Diclofenac, tramadol, piroxicam, meloxicam,tenoxicam, droxicam, lornoxicam, isoxicam, mefanamic acid, meclofenamicacid, flufenamic acid, tolfenamic, valdecoxib, parecoxib, etodolac,indomethacin, aspirin, ibuprophen, firocoxib.

Disease-modifying antirheumatic drugs (DMARDs) useful in combinationwith the IL-17 antagonist (e.g., secukinumab) for the treatment of RApatients, e.g., high risk RA patients, include, methotrexate (MTX),antimalarial drugs (e.g., hydroxychloroquine and chloroquine),sulfasalazine, Leflunomide, azathioprine, cyclosporin, gold salts,minocycline, cyclophosphamide, D-penicillamine, minocycline, auranofin,tacrolimus, myocrisin, chlorambucil.

Biologic agents useful in combination with the IL-17 antagonist (e.g.,secukinumab) for the treatment of RA patients, e.g., high risk RApatients, include, ADALIMUMAB (Humira®), ETANERCEPT (Enbrel®),INFLIXIMAB (Remicade®; TA-650), CERTOLIZUMAB PEGOL (Cimzia®; CDP870),GOLIMUMAB (Simponi®; CNTO148), ANAKINRA (Kineret®), RITUXIMAB (Rituxan®;MabThera®), ABATACEPT (Orencia®), TOCILIZUMAB (RoActemra/Actemra®).

Other biological agents useful in combination with the IL-17 antagonist(e.g., secukinumab) for the treatment of RA patients, e.g., high risk RApatients, include, e.g., integrin antagonist (TYSABRI® (natalizumab)),IL-1 antagonists (ACZ885 (Ilaris)), Anakinra (Kineret®)), CD4antagonists, IL-17 antagonists (LY2439821, RG4934, AMG827, SCH900117,R05310074, MEDI-571, CAT-2200), IL-23 antagonists, IL-20 antagonists,IL-6 antagonists, TNF alpha antagonists (e.g., TNF alpha antagonists orTNF alpha receptor antagonsits, e.g., pegsunercept, etc.), BLySantagonists (e.g., Atacicept, Benlysta®/LymphoStat-B® (belimumab)), P38Inhibitors, CD20 antagonists (Ocrelizumab, Ofatumumab (Arzerra®)),Interferon gamma antagonists (Fontolizumab).

Steroids (e.g., glucocorticoids) useful in combination with the IL-17antagonist (e.g., secukinumab) for the treatment of RA patients, e.g.,high risk RA patients, include, Prednisolone, Prednisone, dexamethasone,cortisol, cortisone, hydrocortisone, methylprednisolone, betamethasone,triamcinolone, beclometasome, fludrocottisone, deoxycorticosterone,aldosterone

Other agents useful in combination with the IL-17 antagonist (e.g.,secukinumab) for the treatment of RA patients, e.g., high risk RApatients, include, SB-681323, Rob 803, AZD5672, AD 452, SMP 114,HZT-501, CP-195,543, Doxycycline, vancomycin, CRx-102, AMG108,pioglitazone, SBI-087, SCIO-469, Cura-100, Oncoxin+Viusid, TwHF,PF-04171327, AZD5672, Methoxsalen, ARRY-438162, VitaminD—ergocalciferol, Milnacipran, Paclitaxel, GW406381, rosiglitazone,SC12267 (4SC-101); LY2439821, BTT-1023, ERB-041, ERB-041, KB003, CF101,ADL5859, MP-435, ILV-094, GSK706769, GW856553, ASK8007, MOR103, HE3286,CP-690,550 (tasocitinib), REGN88 (SAR153191), TRU-015, BMS-582949,SBI-087, LY2127399, E-551S-551, H-551, GSK3152314A, RWJ-445380,Tacrolimus (Prograf®), RAD001, rapamune, rapamycin, fostamatinib,Fentanyl, XOMA 052, CNTO 136, JNJ 38518168, Imatinib, ATN-103, ISIS104838, folic acid, folate, TNFa kinoid, MM-093, type II collagen,VX-509, AMG 827 70, masitinib (AB1010), LY2127399, cyclosporine,SB-681323, MK0663, NNC 0151-0000-0000, ATN-103, CCX 354-C, CAM3001,LX3305, Cetrorelix, MDX-1342, TMI-005, MK0873, CDP870, Tranilast, CF101,mycophenolic acid (and esters thereof), VX-702, GLPG0259, SB-681323,BG9924, ART621, LX3305, T-614, Fostamatinib disodium (R935788), CCI-779,ARRY-371797, CDP6038, AMG719, BMS-582949, GW856553, rosiglitazone,CH-4051, CE-224,535, GSK1827771, GW274150, BG9924, PLX3397, TAK-783,INCB028050, LY2127399, LY3009104, R788, Curcumin (Longvida™)Rosuvastatin, PRO283698, AMG 714, MTRX1011A, Maraviroc, MEDI-522,MK0663, STA 5326 mesylate, CE-224,535, AMG108, BG00012, ramipril,VX-702, CRx-102, LY2189102, SBI-087, SB-681323, CDP870, Milnacipran, PD0360324, PH-797804, AK106-001616, PG-760564, PLA-695, MK0812, ALD518,Cobiprostone, somatropin, tgAAC94 gene therapy vector, MK0359, GW856553,esomeprazole, everolimus, trastuzumab, bone anabolics and boneanti-resorptives (e.g., PTH, bisphosphonates (e.g., zoledronic acid),JAK1 and JAK2 inhibitors, pan JAK inhibitors, e.g., tetracyclic pyridone6 (P6), 325, PF-956980, sclerostin antagonists (e.g., disclosed inWO09047356, W02000/32773, WO2006102070, US20080227138, US20100028335, US20030229041, WO2005003158, WO2009039175 WO2009079471, WO03106657,WO2006119062, WO08115732, WO2005/014650, WO2005/003158, WO2006/119107,WO2008/061013, WO2008/133722, WO2008/115732, U.S. Pat. Nos. 7,592,429,7,879,322, 7,744,874, the contents of which are incorporated byreference herein in their entirety [preferred anti-sclerostin antibodiesand antigen binding fragments thereof for use in the disclosed methods,pharmaceutical compositions, kits and uses are found in WO09047356(equivalent to U.S. Pat. No. 7,879,322), WO06119107 (equivalent to U.S.Pat. Nos. 7,872,106 and 7,592,429) and WO08115732 (equivalent to U.S.Pat. No. 7,744,874]), denosumab, IL-6 antagonists, CD20 antagonistis,CTLA4 antagnonists, IL-17 antagonists, IL-8 antagnoists, IL-21antagonistis, IL-22 antagonist, integrin antagonists (Tysarbri®(natalizumab)), scleronstin antagonists, VGEF antagnosits, CXCLantagonists, MMP antagonists, defensin antagonists, IL-1 antagonists(including IL-1 beta antagonsits), and IL-23 antagonists (e.g., receptordecoys, antagonistic antibodies, etc.).

In some embodiments, the IL-17 antagonist (e.g., secukinumab) isadministered in combination with at least one anti-rheumatic agentselected from the group consisting of an immunosuppressive agent, aDMARD, a pain-control drug, a steroid, a NSAID, a cytokine antagonist, abone anabolic, a bone anti-resorptive, and combinations thereof. In someembodiments, the IL-17 antagonist (e.g., secukinumab) is administered incombination with a TNF antagonist, a DMARD (e.g., MTX, e.g., weeklydoses of 7.5-30 mg)), a steroid, or combinations thereof.

A skilled artisan will be able to discern the appropriate dosages of theabove agents for co-delivery with the IL-17 antagonist (e.g.,secukinumab).

Kits and Articles of Manufacture

Disclosed herein are kits (i.e., an article of manufacture) useful forproviding an IL-17 antagonist, e.g., IL-17 binding molecule (e.g., IL-17antibody or antigen binding fragment thereof, e.g., secukinumab) orIL-17 receptor binding molecule (e.g., IL-17 antibody or antigen bindingfragment thereof), for the treatment of RA. Such kits may comprise anIL-17 antagonist (e.g., secukinumab) (e.g., in liquid or lyophilizedform) or a pharmaceutical composition comprising the IL-17 antagonist(e.g., secukinumab). Additionally, such kits may comprise means foradministering the IL-17 antagonist (e.g., secukinumab) (e.g., a syringeor a prefilled pen) and instructions for use. These kits may containadditional therapeutic agents (described supra) for treating RA, e.g.,for delivery in combination with the enclosed IL-17 antagonist (e.g.,secukinumab).

Disclosed herein are kits comprising: a) an IL-17 antagonist, e.g.,IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof); b) instructions foradministering the IL-17 antagonist (e.g., secukinumab), to a high riskRA patient; c) means for administering the IL-17 antagonist (e.g.,secukinumab) to the patient; and d) optionally, a therapeuticallyeffective amount of at least one anti-rheumatic agent selected from thegroup consisting of an immunosuppressive agent, a disease-modifyinganti-rheumatic drug (DMARD), a pain-control drug, a steroid, anon-steroidal anti-inflammatory drug (NSAID), a cytokine antagonist, abone anabolic, a bone anti-resorptive, and combinations thereof. In someembodiments the high risk RA patient: a) is RF+, ACPA+, or both RF+ andACPA+; and b) has a high level of CRP, a high ESR, or both a high levelof CRP and a high ESR.

Disclosed herein are kits comprising: a) an IL-17 antagonist, e.g.,IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab), or IL-17 receptor binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof) or a pharmaceuticalcomposition comprising an IL-17 antagonist, for use in the treatment ofrheumatoid arthritis (RA) in a patient; and b) instructions describinghow to administer said pharmaceutical composition to the patient,wherein the patient is characterized as: i) being RF+, ACPA+, or bothRF+ and ACPA+; and ii) having a high level of CRP, a high ESR, or both ahigh level of CRP and a high ESR.

Also disclosed herein are in vitro test methods for selecting a patientfor treatment of RA, comprising determining if: i. the patient is RF+,ACPA+, or both RF+ and ACPA+; and ii. the patient has a high level ofCRP, a high ESR, or both a high level of CRP and a high ESR. In someembodiments of the test method, the patient is expected to have animproved therapeutic response to the following regimen: a) either i)administering the patient three doses of about 10 mg/kg of an IL-17antagonist, e.g., IL-17 binding molecule (e.g., IL-17 antibody orantigen binding fragment thereof, e.g., secukinumab), or IL-17 receptorbinding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof), the first dose being delivered during week zero, the seconddose being delivered during week two, and the third dose being deliveredduring week four or ii) administering the patient weekly doses of about75 mg or about 150 mg of an IL-17 antagonist, e.g., IL-17 bindingmolecule (e.g., IL-17 antibody or antigen binding fragment thereof,e.g., secukinumab), or IL-17 receptor binding molecule (e.g., IL-17antibody or antigen binding fragment thereof) for four or five(preferably five) doses; and b) thereafter administering the patientabout 75 mg-about 300 mg of the IL-17 antagonist twice a month, monthly,every two months or every three months (preferably monthly), beginningduring week eight. These in vitro methods may be performed on biologicalsamples (e.g., blood, cartilage, bone, serum, etc.) extracted from thepatient and may be used in determining the mode or course of treatmentfor a particular patient, e.g., whether to administer the IL-17antagonist to the patient (alone or in combination with anothercompound, e.g., such as methotrexate), or whether to choose alternativetherapies (e.g., anti-TNF treatment).

Diagnostic Methods and Methods of Producing a Transmittable Form ofInformation

Disclosed herein are methods for determining (predicting) the likelihoodthat an RA patient will respond favorably (e.g., reduced sign andsymptoms, reduced joint damage, increased quality of life, etc.) totreatment with an IL-17 antagonist, e.g., IL-17 binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof, e.g., secukinumab)or IL-17 receptor binding molecule (e.g., IL-17 antibody or antigenbinding fragment thereof). Such methods will help physicians determine acourse of treatment for a particular RA patient.

Disclosed herein are also methods of determining the likelihood that anRA patient will respond to treatment with an IL-17 antagonist, e.g.,IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof), comprising assayinga sample from the patient for: a) rheumatoid factor (RF),anti-citrullinated protein antibody (ACPA), or RF and ACPA; and b)C-reactive protein (CRP), an erythrocyte sedimentation rate (ESR), orboth CRP and an ESR, wherein the patient is likely to respond totreatment of RA with the IL-17 antagonist (e.g., secukinumab) if thepatient is RF+, ACPA+, or RF+ and ACPA+; and the patient has a highlevel of CRP, a high ESR, or a high level of CRP and a high ESR then thepatient. In some embodiments, prior to the step of assaying, a sample isfirst obtained from the patient (e.g., by extracting blood or otherbiological tissue from the patient).

Disclosed herein are also methods of predicting the likelihood that anRA patient will respond to treatment with an IL-17 antagonist, e.g.,IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof) comprising,determining whether a patient: a) is RF+ and/or ACPA; and 2) has a highlevel of CRP and/or a high ESR, wherein the patient has an increasedlikelihood or responding to treatment with the IL-17 antagonist if thepatient is RF+, ACPA+, or RF+ and ACPA+; and has a high level of CRP, ahigh ESR, or a high level of CRP and a high ESR. In some embodiments,prior to the step of determining, a sample is first obtained from thepatient (e.g., by extracting blood or other biological tissue from thepatient).

Disclosed herein are also methods of determining the likelihood that anRA patient will respond to treatment with an IL-17 antagonist, e.g.,IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragmentthereof, e.g., secukinumab) or IL-17 receptor binding molecule (e.g.,IL-17 antibody or antigen binding fragment thereof) comprising, assayinga sample from the patient for the baseline level of C-reactive protein(CRP), wherein the patient is likely to respond to treatment of RA withthe IL-17 antagonist (e.g., secukinumab) if the patient has elevatedbaseline CRP. In some embodiments, prior to the step of assaying, asample is first obtained from the patient (e.g., by extracting blood orother biological tissue from the patient).

For these diagnostic and prognostic methods, a sample from the patientmay be assayed by any conventional means for detecting the factor (RF,ACPA, CRP, ESR) or level of factor, e.g., radial immunodiffusion,electroimmunoassay, immunoturbidimetry, Western blot, Northern blot,ELISA, turbidimetric methods, fluorescence polarization immunoassay,laser nephelometry, an agglutination test, a nephelometry test,measuring the distance that red blood cells precipitate in a tube overtime (e.g., in the case of ESR), etc. The terms “assaying” and“determining” contemplate a transformation of matter, e.g., atransformation of a biological sample, e.g., a blood sample or othertissue sample, from one state to another by means of subjecting thatsample to physical testing. Further, as used herein, the terms“assaying” and “determining” are used to mean testing and/or measuring.The phrase “assaying a sample from the patient for . . . ” and the likeis used to mean that a sample may be tested (either directly orindirectly) for either the presence or nonpresence of a given factor orfor the level of a particular factor. It will be understood that, in asituation where the presence of a substance denotes one probability andthe absence of a substance denotes a different probability, then eitherthe presence or the absence of such substance may be used to guide atherapeutic decision. In some embodiments, prior to treatment with theIL-17 antagonist, a skilled clinician will determine whether a patientis a high risk RA patient.

Typically, once the presence or absence of a particular factor, or thelevel of a particular factor is identified, physicians or geneticcounselors or patients or other researchers may be informed of theresult. Specifically, the result can be cast in a transmittable form ofinformation that can be communicated or transmitted to other researchersor physicians or genetic counselors or patients. Such a form can varyand can be tangible or intangible. The result with regard to thepresence or absence of RF and/or ACPA, and/or the level of CRP and/orESR in the individual tested can be embodied in descriptive statements,diagrams, photographs, charts, images or any other visual forms. Forexample, images of gel electrophoresis of PCR products can be used inexplaining the results. The statements and visual forms can be recordedon a tangible media such as papers, computer readable media such asfloppy disks, compact disks, etc., or on an intangible media, e.g., anelectronic media in the form of email or website on internet orintranet. In addition, the result with regard to the presence or absenceof RF and/or ACPA, and/or the level of CRP and/or ESR in the individualtested can also be recorded in a sound form and transmitted through anysuitable media, e.g., analog or digital cable lines, fiber optic cables,etc., via telephone, facsimile, wireless mobile phone, internet phoneand the like. All such forms (tangible and intangible) would constitutea “transmittable form of information”. Thus, the information and data ona test result can be produced anywhere in the world and transmitted to adifferent location. For example, when a genotyping assay is conductedoffshore, the information and data on a test result may be generated andcast in a transmittable form as described above. The test result in atransmittable form thus can be imported into the U.S. Accordingly, thepresent disclosure also encompasses a method for producing atransmittable form of information on the presence or absence of RFand/or ACPA, and/or the level of CRP and/or ESR in an individual.

Disclosed herein are methods for producing a transmittable form ofinformation on a patient having RA, comprising: a) assaying a samplefrom the patient for: i) rheumatoid factor (RF), anti-citrullinatedprotein antibody (ACPA), or RF and ACPA; and ii) C-reactive protein(CRP), an erythrocyte sedimentation rate (ESR), or both CRP and an ESR;and b) embodying the result of the assaying step in a transmittable formof information. In some embodiments, following the step of embodying, ahealth care provider (e.g., physician) uses the transmittable form ofinformation in making a decision to prescribe one of the treatmentregimens disclosed herein, using the IL-17 antagonists disclosed herein.In some embodiments, following the step of embodying, a health careprovider (e.g., physician) administers an IL-17 antagonist to thepatient if the transmittable form of information identifies the patientas a high risk RA patient.

General

All patents, published patent applications, publications, references andother material referred to herein are incorporated by reference hereinin their entirety. The details of one or more embodiments of thedisclosure are set forth in the accompanying description above. Althoughany methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present disclosure,the preferred methods and materials are now described. Other features,objects, and advantages of the disclosure will be apparent from thedescription and from the claims. In the specification and the appendedclaims, the singular forms include plural referents unless the contextclearly dictates otherwise. Unless defined otherwise, all technical andscientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this disclosurebelongs. All patents and publications cited in this specification areincorporated by reference. The following Examples are presented in orderto more fully illustrate the preferred embodiments of the disclosure.These examples should in no way be construed as limiting the scope ofthe disclosed patient matter, which is defined by the appended claims.

EXAMPLES Example 1: Use of Secukinumab to Treat Rheumatoid Arthritis(RA) (CAIN457F2201) Example 1.1—Study Design

The study population consists of a representative group of patients(male or non-pregnant, nonlactatin females) of at least 18 years of age,fulfilling ACR 1987 revised classification criteria for RA for at least3 months. Eligible patients were required to present active RA definedby ≥6 out of 28 tender joints and ≥6 out of 28 swollen joints, andhsCRP≥10 mg/L OR ESR≥28 mm/1st hour (mm/h) at the time of randomizationto assure ability to detect response to treatment using ACR criteria.Eligible candidates were on MTX for at least 3 months and at selectionwere currently treated with a stable weekly dose of MTX (≥7.5mg/week-≤25 mg/week) for at least 4 weeks.

Adult RA patients (n=237) on methotrexate were randomized equally toreceive monthly s.c. injections of secukinumab 25 mg, 75 mg, 150 mg, 300mg or placebo. Patients with previous exposure to biologics wereincluded in all cohorts (18-22%). The primary end point was theproportion of patients achieving American College of Rheumatology (ACR)20 at week 16. At Week 20 (Visit 8), patients who were randomized toplacebo at Week 0 or who were randomized to secukinumab but did notachieve an ACR20 response at Week 16 were re-assigned to receive doubleblind treatment up to Week 48, with a final efficacy assessmentperformed at Week 52, and a follow up visit at Week 60, as followsstarting at Week 20 (FIG. 1):

-   -   Patients on active treatment who were responders continued on        their dose regimen;    -   All placebo patients were switched to active treatment 150 mg        s.c. q4 wk (monthly), independent of disease activity;    -   All patients treated with 25 mg or 75 mg secukinumab q4 wk who        were non-responders were switched to 150 mg s.c. q4 wk;    -   Non-responders in the 150 mg group were switched to the next        highest dose—300 mg s.c. q4 wk;    -   All patients on 300 mg group remained on their respective dose        to assess if exposure longer than 16 weeks will induce a        clinical response in these patients.

Efficacy assessments are ACR20, 50, 70 (Felson et al. (1995) ArthritisRheum; 38(6):727-35) and DAS28 response/remission (Fransen et al (2003)Ann Rheum Dis; 62(Suppl 1): 10; Prevoo et al. (1995) Arthritis Rheum;38(1):44-48). The primary efficacy variable is the clinical response totreatment according to ACR20 individual improvement in disease activityat Week 16. Results are assessed by the proportion of patients achievingthe ACR20 response criteria at Week 16. A patient will be considered aresponder according to ACR20 criteria if he/she has:

A) at least 20% improvement in the two following measures:

-   -   tender 28-joint count    -   swollen 28-joint count; and

B) at least 20% improvement in at least 3 of the following 5 measures:

-   -   Patient's assessment of RA pain (VAS 100 mm)    -   Patient's global assessment of disease activity (VAS 100 mm)    -   Physician's global assessment of disease activity (VAS 100 mm)    -   Patient self-assessed disability (Health Assessment        Questionnaire [HAQ©] score)    -   Acute phase reactant (C-reactive protein [hsCRP] or erythrocyte        sedimentation rate (ESR))        Additional measures include: ACR50 (50% improvement in item B        (above) in at least 3 of the 5 measures and 50% improvement in        the swollen and tender joint count) and ACR70 (70% improvement        in item B (above) in at least 3 of the 5 measures and 70%        improvement in the swollen and tender joint count).

The DAS28 (Disease Activity Score—28) is a well-established measure ofdisease activity in RA. The score is calculated by a complexmathematical formula, which includes the number of tender and swollenjoints (out of a total of 28), the erythrocyte sedimentation rate (ESR)or hsCRP, and the patient's global assessment of global health(indicated by marking a 100 mm line between very good and very bad). ADAS28 score greater than 5.1 implies active disease, less than 3.2 wellcontrolled disease, and less than 2.6 remission.

In order to calculate the DAS28, information about the following diseasevariables is needed:

-   -   The number of swollen joints and tender joints should be        assessed using 28-joint count (tender28 and swollen28).    -   The erythrocyte sedimentation rate (ESR) should be measured in        mm/hour.    -   The patient's general health (GH) or global disease activity        measured on a Visual Analogue Scale (VAS) of 100 mm (both are        useable for this purpose) must be obtained.

Using this data, the DAS28 can be calculated using the followingformula:

DAS28=0.56*sqrt(tender28)+0.28*sqrt(swollen28)+0.70*ln(ESR)+0.014*GH

C-reactive protein (CRP) may be used as an alternative to ESR in thecalculation of the DAS or DAS28, using the formulas below. CRP is a moredirect measure of inflammation than ESR, and it is more sensitive toshort-term changes. CRP production is associated with radiologicalprogression in RA, and is considered at least as valid as ESR to measureRA disease activity. Another advantage of determination of CRP is thatwaiting time for the laboratory result is shorter and that in case ofmulticenter studies a central laboratory can be used. The followingformulas to calculate the DAS28 using CRP (mg/L) give good estimationsof the original DAS28 values on a group level.

DAS28-4(crp)=0.56*sqrt(TJC28)+0.28*sqrt(SJC28)+0.36*ln(CRP+1)+0.014*GH+0.96

TJC28: 28 Tender joint count; SJC28: 28 Swollen joint count; CRP:C-reactive protein; GH: General Health on a 100 mm. Visual AnalogueScale.

The HAQ© is a validated measure of physical disability and functionalstatus. It has four dimensions: disability, pain, drug side effects anddollar costs, although, the latter three are rarely used in clinicaltrials. In this trial only the disability dimension was used. Thedisability dimension consists of 20 multiple choice items concerningdifficulty in performing eight common activities of daily living;dressing and grooming, arising, eating, walking, reaching, personalhygiene, gripping and activities. Subjects choose from four responsecategories, ranging from ‘without any difficulty’ to ‘unable to do’. TheACR Rheumatology Committee on Outcome Measures in RA recommends the useof this questionnaire in clinical trials. The HAQ© is scored inaccordance with the recommendation from the developers outlined in the“HAQ PACK” from Stanford University, California.

Example 1.2—Statistical Analysis

To test superiority of secukinumab treatment groups over placebo, theACR20 responder rate (proportion) was compared against placebo for eachof the secukinumab-treated groups based on a logistic regression modelwith treatment, center and baseline DAS28 as covariates. The DAS28-CRPchange from baseline was analyzed using an analysis of covariance(ANCOVA, SAS PROC MIXED) fixed effects model with treatment as maineffect and correcting for the covariates center and baseline value. Allstatistical tests for pairwise comparisons of secukinumab treatmentgroups vs placebo were performed at two-sided 5% significance level. Themethod of last observation carried forward (LOCF) was used for missingvalues for efficacy variables. Figures were produced presenting responseover time or at specific time points up to Week 16 (or Week 52, asappropriate). Of note, for figures presenting results up to Week 52,only data from patients continuing at Week 24 were included.

The full analysis set (FAS) was used for the reporting of the efficacyresults. The FAS comprised all patients to whom study drug had beenassigned. Following the intent-to-treat (ITT) principle, patients wereanalyzed according to the treatment and stratum they were assigned to atrandomization.

Example 1.3—Week 16 Results

Demographics and baseline characteristics were comparable across allgroups. ACR20 responders at Week 16 were higher in the secukinumab 75mg, 150 mg and 300 mg dose groups (46.9%, 46.5% and 53.7%, respectively)compared to placebo (36.0%) and compared to secukinumab 25 mg (34%)(FIG. 2A). However, these results did not achieve statisticalsignificance due to a marked and unexplained increase in ACR20 in theplacebo group between Week 12 (24%) and 16 (36%). Clinically relevantreductions in DAS28-CRP were observed in the secukinumab 75-300 mgtreatment groups vs. placebo (FIG. 5A). Serum CRP levels at Week 16 weremarkedly reduced in secukinumab 75-300 mg groups vs. placebo (p=0.0012,0.0081 and 0.0241) (data not shown). ACR50 and ACR70 showed consistentgreater improvements with secukinumab 75-300 mg doses vs. placebo over16 weeks (FIGS. 3A and 4A). There was about a 4-fold average reductionfrom baseline in the HAQ© score at week 16 in the 150-300 mg groupscompared to placebo (FIG. 6A).

Example 1.4—Week 24 Results

By Week 24, ACR20 responses were maintained and DAS28 CRP responsesfurther improved in the 75-300 mg groups with secukinumab treatmentbetween week 16 and 24. HAQ© scores were either maintained or furtherreduced in the 75-300 mg groups with groups with secukinumab treatmentbetween week 16 and 24. The 75-300 mg ACR20 responder treatment groupsexhibited an early improvement in HAQ© scores over time through Week 24.ACR50 responses further improved from 19-24% (75 mg), 21-25% (150 mg)and 19-24% (300 mg) in patients originally randomized to the respectivedose cohorts, part of whom had a dose escalation at Week 20; a similarimprovement was seen in ACR70 responses in the 75 mg-150 mg groups. Anincrease in the ACR20/50/70 response in the patients randomized toplacebo between Week 16 and 24 can also be noted. All patients onplacebo up to Week 16 were switched to secukinumab 150 mg at Week 20.

Example 1.5—Week 52 Results

With respect to efficacy of secukinumab over time patients who had beenresponders at week 16 generally maintained their responses in terms ofACR 20 (FIG. 2C), ACR50 (FIG. 3B) and ACR70 (FIG. 4B) with bestresponses seen in the 150 mg responder cohort. The same was also truefor DAS28-CRP and HAQ scores responses which were maintained inresponders at week 16 over time through week 52 again with bestresponses observed in the 150 mg responder cohort (Figure. 5B, 6B).ACR20, 50 and 70 responses at week 52 are shown in FIG. 7 again withhighest responses for all these parameters in the 150 mg respondercohort.

Biological failure patients were 18-22% in each cohort at study start.Of patients previously exposed to biologics who were dosed with 150 mgsecukinumab after Week 20, 62% (8 of 13) achieved an ACR20, 38% (5 of13) achieved an ACR50 and 23% achieved an ACR 70 at Week 52. Thisprovides evidence that secukinumab is capable of treating RA in patientswho failed anti-TNF and other biological therapy.

Example 2: Analysis of High Risk RA Patient Subset in CAIN457F2201Example 2.1—Statistical Analysis

In searching for indicators predictive of an RA patient's response totreatment with secukinumab, we analyzed two of the four 2010 ACR/EULARscoreable criteria (see Table 1) to determine how (and whether) thesecriteria may influence response to treatment with secukinumab with datafrom the CAIN457F2201 trial database. First, we analyzed serology todetermine whether the patient is RF+ and/or anti-CCP+(i.e., ACPA+).Second, we analyzed the presence of acute-phase reactants to determinewhether the patient has a high level of C-reactive protein (CRP) and/ora high erythrocyte sedimentation rate (ESR).

Analysis was mainly performed with summary statistics (proportions forbinary response variables and average for continuous variables) producedover time to observe responses up to Week 16 (or 52, for patients whocontinued at Week 24). The method of last observation carried forward(LOCF) was used for missing values for efficacy variables. Data wereproduced presenting response over time or at specific time points up toWeek 16 (or Week 52, as appropriate). Of note, for data showing resultsup to Week 52, only data from patients continuing at Week 24 wereincluded.

Example 2.2—Analysis of Responses to Secukinumab in High Risk RAPatients

The analysis of subgroup of patients with “high risk” (i.e., “high riskRA patients”) for disease progression (based on high CRP and/or ESR, andpositive RF and/or ACPA) showed promising results in the secukinumabtreated patients compared to the CAIN457F2201 overall trial results,while the responses in the placebo group did not show similar increasedtrend. In terms of ACR20, in the FAS, 46.9, 46.5, 53.7 and 36% responsewas observed at Week 16 in the secukinumab 75, 150, 300 mg and placebo(FIG. 2A and Table 6), respectively, whereas 48.8, 57.6, 58.1 and 41.0%responses was observed at Week 16 in the high risk subgroup (FIG. 2B andTable 6). Similarly, increased response rates were observed at Weeks 16and 52 in the high risk subgroup compared to the FAS, and in othervariables such as ACR50/70 (Table 6), DAS28-CRP (Table 7), and HAQ©(data not shown).

Summaries of ACR20/50/70% and DAS28-CRP responses at weeks 16 and 52 inthe FAS, the high risk RA patients, and the non-high risk RA patientsare provided in Table 6 (ACR) and Table 7 (DAS28-CRP). Graphicaldepiction of the ACR20/50/70% and DAS28-CRP responses at week 16 in thehigh risk RA patients and the non-high risk RA patients are provided inFIGS. 8A and 8B.

TABLE 6 ACR responses (LOCF) at weeks 16 and 52 in FAS. high risk RApatients, and non high risk RA patients. ACR Responses Placebo 25 mg 75mg 150 mg 300 mg Week 16 FAS ACR20 18/50 (36.0%) 18/53 (34.0%) 23/49(46.9%) 20/43 (46.5%) 22/41 (53.7%) ACR50 3/50 (6.0%) 8/53 (15.1%) 9/49(18.4%) 9/43 (20.9%) 7/41 (17.1%) ACR70 0/50 (0.0%) 4/53 (7.5%) 1/49(2.0%) 2/43 (4.7%) 2/41 (4.9%) High risk RA ACR20 16/39 (41.0%) 15/44(34.1%) 21/43 (48.8%) 19/33 (57.6%) 18/31 (58.1%) patient ACR50 2/39(5.1%) 7/44 (15.9%) 8/43 (18.6%) 8/33 (24.2%) 5/31 (16.1%) subgroupACR70 0/39 (0.0%) 3/44 (6.8%) 1/43 (2.3%) 2/33 (6.1%) 1/31 (3.2%) NonHigh riskRA ACR20 2/11 (18.2%) 3/9 (33.3%) 2/6 (33.3%) 1/10 (10.0%) 4/10(40.0%) patient ACR50 1/11 (9.1%) 1/9 (11.1%) 1/6 (16.7%) 1/10 (10.0%)2/10 (20.0%) subgroup ACR70 0/11 (0.0%) 1/9 (11.1%) 0/6 (0.0%) 0/10(0.0%) 1/10 (10.0%) Week 52 FAS ACR20 27/44 (61.4%) 18/45 (40.0%) 26/46(56.5%) 26/43 (60.5%) 17/37 (45.9%) ACR50 17/44 (38.6%) 5/45 (11.1%)13/46 (28.3%) 13/43 (30.2%) 5/37 (13.5%) ACR70 5/44 (11.4%) 2/45 (4.4%)5/46 (10/9%) 4/43 (9.3%) 3/37 (8.1%) High risk RA ACR20 22/33 (66.7%)18/38 (47.4%) 20/40 (50.0%) 24/33 (72.7%) 12/28 (42.9%) patient ACR5014/33 (42.4%) 4/38 (10.5%) 11/40 (27.5%) 13/33 (39.4%) 5/28 (17.9%)subgroup ACR70 5/33 (15.2%) 2/38 (5.3%) 4/40 (10.0%) 10/33 (30.3%) 2/28(7.1%) Non High risk RA ACR20 5/11 (45.5%) 3/7 (42.9%) 3/6 (50.0%) 3/10(30.0%) 4/9 (44.4%) patient ACR50 3/11 (27.3%) 1/7 (14.3%) 2/6 (33.3%)1/10 (10.0%) 3/9 (33.3%) subgroup ACR70 0/11 (0.0%) 1/7 (14.3%) 1/6(16.7%) 0/10 (0.0%) 1/9 (11.1%)

TABLE 7 DAS28-ESR median change from baseline at weeks 16 and 52 in FAS,high risk RA patients, and non high risk RA patients. Median change frombaseline in DAS28-ESR Placebo 25 mg 75 mg 150 mg 300 mg Week 16 FAS−0.97 −0.84 −1.40 −1.23 −1.38 High risk RA −1.00 −0.65 −1.22 −1.81 −1.23patient subgroup Non High risk RA −0.88 −1.17 −1.33 −0.27 −0.77 patientsubgroup Week 52 FAS −1.68 −1.31 −1.51 −2.19 −1.33 High risk RA −2.00−1.33 −1.51 −2.87 −1.36 patient subgroup Non High risk RA −1.07 −1.11−1.40 −1.43 −1.29 patient subgroup

Note, for Table 6 and 7, week 52 data is presented by the originalassigned treatment. Titration was performed for ACR20 non-responders(and all placebo patients) starting at week 16. 18/45 ‘original’ 25 mgpatients remained on 25 mg while 27 patients were up-titrated to 150 mg.Likewise, 23/46 ‘original’ 75 mg patients remained on 75 mg while 23were up-titrated to 150 mg. 20/43 ‘original’ 150 mg patients remained on150 mg and 23 were up-titrated to 300 mg. All 44 ‘original’ placebopatients were switched to 150 mg and all ‘original’ 300 mg patientsremained on 300 mg.

As can be seen from Tables 6 and 7, as well as FIGS. 8A and 8B, highrisk RA patients generally display an improved response to IL-17inhibition in comparison to non-high risk RA patients. Comparing theACR20% and ACR50% response between the high risk RA patients andnon-high risk RA patients at week 16 (Table 6 and FIG. 8A), a doseresponse can be seen in the high risk RA patients in response to IL-17inhibition by secukinumab. A similar dose response is seen in theDAS28-CRP score in high risk RA patients at weeks 16 and 52 (Table 7 andFIG. 8B). Furthermore, ACR20% responses at week 16 in the high risk RApatient subset are improved at all doses of secukinumab above 25 mg incomparison to the ACR20% responses seen in non-high risk RA patients(Table 6 and FIG. 8A). In addition, the ACR50/70% response at weeks 16and 52 in high risk RA patients treated with 150 mg secukinumab ishigher than the ACR50/70% response in non-high risk RA patients treatedwith the same secukinumab dose. A similar result is seen in theDAS28-CRP score for 150 mg secukinumab at weeks 16 and for all doses ofsecukinumab at week 52 (Table 7 and FIG. 8B).

Example 3: Patients with Elevated Baseline CRP Benefit from SecukinumabExample 3.1—Study Design

To evaluate the dose-response relationship of DAS28 and ACR responses atweek 16 by baseline high sensitivity (hs) CRP levels in patients with RAtreated with different doses of secukinumab compared to placebo.

As described previously, in study CAIN457F2201, adult RA patients(n=237) on methotrexate were randomized to receive monthly s.c.injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg, or placebo. Weassessed dose relationship of DAS28 and ACR responses at week 16 bydifferent baseline hsCRP levels (≥0 mg/L, ≥10 mg/L, ≥20 mg/L, and ≥30mg/L).

Example 3.2—Results

Demographics and baseline characteristics were comparable across allgroups. A rapid reduction in DAS28-CRP was observed as early as week 2in patients on secukinumab 75 mg, 150 mg, 300 mg groups. By week 12,these patients achieved a clinically meaningful DAS28 reduction of >1.2compared with those on placebo (P<0.05). These responses were sustainedup to week 16 (Table 8). As seen in Table 8 and FIG. 9, there is adose-dependent relationship in DAS28-CRP, ACR20, and ACR50 responses atweek 16 based on baseline hsCRP levels for secukinumab 150 mg and 300 mgdose cohorts in comparison to placebo or secukinumab 25 mg and 75 mggroups. The safety profile of secukinumab up to week 20 was comparableto placebo. Most AEs were mild or moderate in severity and did not leadto study drug discontinuation.

TABLE 8 Dose-response relationship for DAS28-CRP. ACR20, and ACR50 atWeek 16 by CRP levels at baseline. DAS28-CRP, ACR20. and ACR50 data aregiven in median; N: number of patients. “0” = 0 mg/ml, “10” = 10 mg/ml,“20” = 20 mg/ml. “30” = 30 mg/ml. Treatment DAS28/ACR CRP >= 0 CRP >= 10CRP >= 20 CRP >= 30 N 53 25 11 6 Secukinumab DAS28 −1.08 −1.24 −1.46−1.03 25 mg ACR20, % 34 32 36 17 ACR50, % 15 17 19 17 N 49 27 17 10Secukinumab DAS28 −1.40 −1.50 −1.22 −1.46 75 mg ACR20, % 47 49 47 41ACR50, % 19 19 12 10 N 43 20 15 11 Secukinumab DAS28 −1.38 −2.05 −2.13−2.09 150 mg ACR20, % 46 60 67 62 ACR50, % 20 28 31 17 N 41 19 10 6Secukinumab DAS28 −1.30 −1.51 −2.01 −2.21 300 mg ACR20, % 54 64 81 86ACR50, % 17 19 39 67 N 50 26 16 12 Placebo DAS28 −0.83 −0.72 −0.47 −0.67ACR20 0.36 0.31 0.30 0.43 ACR50 0.05 0.03 0.05 0.07

The results indicate that secukinumab provides a rapid reduction ofdisease activity with the greatest improvements seen in those patientson 150 mg or 300 mg who had evidence of high inflammatory burden asevidenced by baseline hsCRP levels. This suggests that secukinumaboffers benefit to RA patients including those with factors renderingthem at high risk for progressive disease.

Example 4: Modeling and Simulation: Rheumatoid Arthritis InductionRegimen Design

The relationship between secukinumab dose/regimen, secukinumab plasmaconcentration and the ACR20 response was modeled using a PK/PD approachdescribing the longitudinal data. These models were used to facilitatedesign of Phase III trials for secukinumab in treating rheumatoidarthritis.

Example 4.1—Methods

Modeling of Secukinumab Pharmacokinetics

For the pharmacokinetic (PK) model (FIG. 10), data from various clinicalstudies (CAIN457A1101, CAIN457A2101, CAIN457A2102, CAIN457A2103,CAIN457A2104, CAIN457A2206, CAIN457A2208, CAIN457A2209 and CAIN457F2201)were pooled. A population approach with a two-compartmental model wasused to describe secukinumab PK. The population parameters wereestimated together with their interindividual variances. The parameterswere: distribution volumes V1=2.96 L and V2=2.52 L, first-orderclearance from the first volume CL=0.169 L/day, intercompartmentalexchange coefficient Q=0.784 L/day, and the absorption rate and absolutebioavailability for a subcutaneous administration were KA=0.192 1/dayand F=76%, respectively. Body weight was identified as a covariate onsecukinumab clearance and volumes.

Modeling of ACR20 Responder Rates in Placebo and Secukinumab TreatmentGroups

For ACR20 modeling data on methotrexate inadequate responder patients(Table 9), data from two clinical studies (CAIN457A2101 andCAIN457F2201) were used. ACR20 responder rates were modeled using aconcentration-responder probability approach for the placebo and treatedgroups. The assumption was that the ACR20 response rate increasedmonotonically until 16 weeks for placebo and treated groups. Themonotonically increasing curve depended on the logarithm of time and thesquare root of secukinumab concentration. The observed ACR20 (LoCF) atweeks, 4 (day 29), 8 (day 57), 12 (day 86) and 16 (day 113) was modeledin two steps for placebo and the treated group.

ACR20 Time Profile Model for Placebo Group

The observed ACR20 at time t_(i) (i=1, 2, 3, 4 denotes week 4, 8, 12 and16) for j-th patient in placebo group was written as:

ACR20_(0j)(t _(i))˜binomial(1,p ₀(t _(i)))

Log it(p ₀(t _(i)))=α+β log(t _(i))/log(t ₄).

Thus the log it of the ACR20 response rate in the placebo group at week16 was α+β and at time 0 it was ˜∞ which corresponds to a probability torespond of 0 at time zero.

ACR20 Time Profile Model for Secukinumab Treated Group

The observed ACR20 at time t_(i) for the j-th patients in secukinumabtreated group was written as:

ACR20_(j)(t _(i))˜binomial(1,p(t _(i)))

Log it(p(t_(i)))=Log it(p₀(t_(i)))+γ(t_(i))h(conc_(j)(t_(i))), where h() was the square root of the individual model predicted concentration.Here γ was the change of sensitivity of ACR20 responder rate to theconcentration at time t_(i).

γ(t _(i))=γ₀ log(t _(i))/log(t ₄).

Hence the effect of secukinumab was described byγ(t_(i))h(conc_(j)(t_(i))). The functional form γ was chosen to be thelog of study day, the same as placebo time effects, in other words aproportional odds in h(conc) was assumed.

The generalized estimating equation method was used for the evaluationand the within patient correlation of the ACR20 observed response wereassumed to be compound symmetry.

Example 4.2—Results Example 4.2.1—PK Modeling Results

As can be seen in FIG. 10, the model predicts that a higher secukinumabplasma concentration can be achieved using either an i.v. or s.c.induction regimen in comparison to no induction regimen. Furthermore,the model further predicts that an induction regimen that uses 10 mg/kgsecukinumab delivered i.v. at weeks 0, 2 and 4 can provide higher plasmaconcentration of secukinumab (and at a more rapid rate) than aninduction regimen that uses 300 mg secukinumab delivered s.c. at weeks0, 1, 2, 3 and 4. The s.c. and i.v. induction regimens modeled providedimproved response in comparison to a dosing regimen lacking an inductionregimen.

Example 4.2.4—ACR20 Simulation Results

The results from the ACR20 responder modeling are presented in Table 9.The ACR20 simulation predicts that a greater ACR20 response rate can beachieved using either an i.v. (63%) or s.c. (57%) induction regimen incomparison to no induction regimen (35%). Furthermore, the model furtherpredicts that an induction regimen that uses 10 mg/kg secukinumabdelivered i.v. at weeks 0, 2 and 4 can provide a greater ACR20 responserate than an induction regimen that uses 300 mg secukinumab delivereds.c. at weeks 0, 1, 2, 3 and 4. The s.c. and i.v. induction regimensmodeled provided improved response in comparison to a dosing regimenlacking an induction regimen.

TABLE 9 Simulated ACR20 responder rates. ACR20 response at Inductionweek 4 with 95% strategy Induction dose - regimen confidence interval Noinduction 300 mg s.c. every 4 weeks 35% (27-46) Induction 300 mg s.c. atWeeks 0, 57% (41-76) using s.c. 1, 2, 3 and 4 followed by dosing 300 mgs.c. every 4 weeks Induction 10 mg/kg i.v. at Weeks 0, 63% (47-81) usingi.v. 2 and 4 followed by 300 mg dosing s.c. every 4 weeks

Example 5: Secukinumab Shows Good Safety and Efficacy in the Treatmentof Active Ankylosing Spondylitis Example 5.1—Study Design CAIN457A2209

CAIN457A2209 is a phase II, multicenter, randomized, double-blind,parallel-group, placebo controlled proof-of-concept study in patientswith moderate to severe AS. The study population is patients of age18-65 years with AS diagnosed according to the modified New Yorkcriteria, back pain & nocturnal pain score ≥4 (0-10 point scale), aBASDAI score ≥4 (0-10 point scale), and inadequate response to currentor previous use of at least one NSAID given over at least 3 months atmaximum recommended dose. Patients with previous TNF-α blocker use wereallowed to enroll after appropriate wash-out periods. Patients wereallowed to continue concurrent treatment with NSAIDS, methotrexate(MTX), sulphasalazine, and prednisolone at stable doses during thestudy. However, patients with evidence of active tuberculosis wereexcluded.

Thirty (30) patients were randomised in a 4:1 ratio to receive two i.vinfusions of either secukinumab (AIN457) 10 mg/kg i.v. or placebo i.v.given 3 weeks apart. Patients will be followed for safety up to week 28.A Bayesian analysis of the Week 6 ASAS20 response rates of AIN457 andplacebo was performed. The prior distributions for the response rateswere specified as Beta distributions and the binomial distribution wasassumed for the observed number of responders in each group. Thepredictive distribution of the placebo response rate from ameta-analysis of 8 randomized, placebo-controlled trials ofanti-TNFalpha treatment in AS was used as the prior distribution for theplacebo response rate. This prior was equivalent to observing 11 out of43 responders (i.e. a response rate of 26%). A weak prior was used forthe active response rate (equivalent to observing 0.5 out of 1.5responders).

Ther primary end point was the proportion of patients achieving theAssessment of Spondylo Arthritisinternational Society (ASAS) 20 responseat week 6.

Example 5.2—Results

Demographics and baseline characteristics were comparable betweengroups. Mean (SD) BASDAI at baseline was 7.1 (1.4) forsecukinumab-treated patients and 7.2 (1.8) for placebo-treated patients.Three patients on placebo and 2 patients on AIN457 discontinued thestudy prior to the primary endpoint, mostly due to unsatisfactorytherapeutic effect. Efficacy data from 1 patient was not available dueto a protocol violation after randomization. At week 6, 14/23secukinumab-treated patients who entered efficacy analysis achievedASAS20 responses versus 1/6 placebo treated patients (61% vs 17%,probability of positive-treatment difference=99.8%, credible interval11.5%, 56.3%). ASAS40 and ASAS5/6 responses of secukinumab-treatedpatients were 30% and 35%, respectively, and mean (range) BASDAI changewas −1.8 (−5.6 to 0.8). In a majority of the ASAS20 responders,secukinumab induced responses within a week of treatment. Thepharmacokinetic profile was as expected for an IgG1 mAb and comparableto secukinumab given for other indications.

The primary endpoint of this study was met, as secukinumab inducedsignificantly higher ASAS20 responses than placebo at week 6. No earlysafety signals were noted in this study population. Interim datapresented here suggests that secukinumab has use in treating activeankylosing spondylitis.

Example 6—Secukinumab Reduces Signs and Symptoms of Psoriatic Arthritisin a 24-Week Multicenter, Double-Blind, Randomized, Placebo-ControlledTrial Example 6.1—Study Design and Demographics

Forty-two patients with active psoriatic arthritis (PsA) fulfillingCASPAR criteria were assigned 2:1 to receive two injections withsecukinumab (10 mg/kg) or placebo, given three weeks apart. The primaryefficacy endpoint was the proportion of ACR20 responders at Week 6 inactive compared with placebo recipients (one-sided p-value <0.1). As perprotocol, no imputation was made for missing data (drop-outs weretreated as missing).

Twenty-five (89%) patients on secukinumab and 10 (71%) on placebocompleted the study. Five patients (4 secukinumab and 1 placebo) wereexcluded from the efficacy analysis due to protocol violations. Three(11%) of patients on secukinumab and 4 (29%) on placebo discontinuedprematurely for lack of efficacy or withdrawal of consent. Demographicsand baseline characteristics were balanced between groups for age, sexand parameters including mean (SD) SJC (secukinumab vs. placebo): 8.3(5.6) vs. 9.5 (5.4); TJC 23.5 (19.4) vs. 22.6 (11.0); DAS28 4.8 (1.2)vs. 4.8 (1.2); MASES 3.0 (4.1) vs. 3.4 (2.3). Co-existing psoriasis,prior TNFi exposure and co-medication with DMARDS were present in 23(98%), 11 (46%) and 21 (88%) patients on secukinumab and in 11 (89%), 5(38%) and 10 (70%) on placebo, respectively.

Example 6.2—Results

The ACR20 response rate at week 6 was 39% (9/23) on secukinumab vs. 23%(3/13) on placebo (P=0.27). ACR20 response rates were 39% (9/23) vs. 15%(2/13) at week 12, and 43% (10/23) vs. 18% (2/11) at week 28 withsecukinumab versus placebo, respectively. ACR50 and ACR70 response ratesat week 6 on secukinumab vs. placebo were 17% vs. 8% and 9% vs. 0%,respectively. CRP reductions at week 6 compared to baseline wereobserved on secukinumab (median [range] of 5.0 [0.3, 43.0] at baselinevs. 3.0 [0.2, 15.2] at week 6, but not on placebo (3.9 [1.3, 39.7] atbaseline vs. 5.0 [0.8, 29.6] at week 6). Similar reductions were seenfor ESR, and reductions in acute phase parameters were maintained up toweek 28. The overall rate of adverse events (AEs) was comparable insecukinumab versus placebo: 26 (94%) vs. 11 (79%). One severe adverseevent (cellulitis hand) occurred on secukinumab, and was not suspectedby the investigator to be study drug-related. Seven serious AEs werereported in 4 secukinumab patients (tendon rupture/carpal tunnelsyndrome/cellulitis, obesity, fall, breast cancer [diagnosed prior todosing and inclusion constituting a protocol violation]) and 1 withplacebo (polyarthritis). Infections were reported in 16 (57%) patientson secukinumab and 7 (50%) patients on placebo.

The safety profile of secukinumab was favorable overall. Although theprimary endpoint was not met, a substantial proportion of patientsshowed rapid and sustained improvements of clinical scores and acutephase parameters up to week 28. Trends towards a beneficial clinicaleffect support the rationale for larger clinical trials designed toassess clinical effectiveness.

Example 7—Pharmokinetic (PK) Information for Seckukinumab

Based on data obtained from various studies, including those discussedin the above Examples, the following PK information has been obtainedfor seckukinumab (Table 10).

TABLE 10 Experimental and simulated pharmokinetic values forsecukinumab. Induction Experimental Average C_(max) 401 μg/ml at end ofthird 10 mg/kg i.v. infusion for a 90 kg human (30%-40% inter- patientvariation) Maintenance (75, 150 or 300 mg s.c. monthly) Averagesteady-state trough levels for a 75 kg human (30% inter-patientvariation): 9.4 μg/ml (e.g., 75 mg dose) 17.3 μg/ml (e.g., 150 mg dose)31 μg/ml (e.g., 300 mg dose) AUC tau ranges at steady state: 314mg*day/L (e.g., 75 mg dose) 628 mg*day/L (e.g., 150 mg dose) 1256mg*day/L (e.g., 300 mg dose) Simulated Average C_(max) 240 μg/ml afterthe first dose and 360 μg/ml after the third i.v. infusion for a 75 kghuman. Trough levels maintained above 80 μg/ml over a 10 week period.Maintenance (75, 150 or 300 mg s.c. monthly beginning week 8) Averagesteady-state trough levels for a 75 kg human: 8.0 μg/ml (e.g., 75 mgdose) 17 μg/ml (e.g., 150 mg dose) 30 μg/ml (e.g., 300 mg dose) AUC tau(mg*day/L) at steady state (The q025 and q975 give the AUC range having95% of the patients): dose Auc_(mean) AUC_(median) AUC_(q025) AUC_(q975)75 331 309 128 657 150 661 618 257 1315 300 1323 1237 513 2629

In addition, it has been determined that secukinumab has a T_(max) ofabout 7-8 days, and an elimination half-life of about 30 days. This PKinformation can be used to design different dosing regimens fortreatment of arthritis, e.g., RA, e.g., high risk RA. Using this PKinformation, one can deliver a different dosage of the IL-17 antagonist,e.g., an IL-17 binding molecule (e.g., an IL-17 antibody, such assecukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17receptor antibody) from the dosages used in the Examples or deliver thesame dosage as used in the Examples, but which is provided at adifferent time point from the time points used in the Examples. Bymaintaining the same PK profile, even though a dosing regimen or adosage may change, a skilled artisan is expected to be able to employ anthe IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17antibody, such as secukinumab) or an IL-17 receptor binding molecule(e.g., an IL-17 receptor antibody) for treatment of arthritis, includingtreatment of high risk RA patients.

Example 8: Pharmaceutical Compositions/Medicaments Comprising an IL-17Antagonist

A formulation study using secukinumab drug substance was initiated withthe aim of developing a product of high strength, e.g., a vial having aunity dose of 150 mg secukinumab. Four sucrose-based formulations, incombination with different stabilizers (mannitol, glycine, arginineHCl), were included in the stability program at real, accelerated andstressed conditions for 12 months (Table 11).

TABLE 11 Formulations included in stablity study AIH457 Stabilizer/ FormConc Buffer Bulking agent Surfactant pH Before lyophilization 1  50mg/mL 10 mM 90 mM Sucrose 0.02% 5.8 Histidine Polysorbate 80 2  50 mg/mL10 mM 20 mM Sucrose, 0.02% 5.8 Histidine 60 mM Mannitol Polysorbate 80 3 50 mg/mL 10 mM 70 mM Sucrose, 0.02% 5.8 Histidine 20 mM GlycinePolysorbate 80 4  50 mg/mL 10 mM 65 mM Sucrose, 0.02% 5.8 Histidine 15mM Arginine Polysorbate 80 After reconstitution of the lyophilisate 1150 mg/mL 30 mM 270 mM Sucrose 0.06% 5.8 Histidine Polysorbate 80 2 150mg/mL 30 mM 60 mM Sucrose, 0.06% 5.8 Histidine 180 mM MannitolPolysorbate 80 3 150 mg/mL 30 mM 210 mM Sucrose, 0.06% 5.8 Histidine 60mM Glycine Polysorbate 80 4 150 mg/mL 30 mM 195 mM Sucrose, 0.06% 5.8Histidine 45 mM Arginine Polysorbate 00

All formulations were filled at 3.6 mL (20% overfill) into 6 mL type Iglass vials, capped with a Flurotec® B2 coated lyo configuration stopperand lyophilized using a conservative lyophilization cycle (Table 12).

TABLE 12 Lyophilization cycle conditions. Time Shelf Chamber StepOperation [hh:mm] Temperature Pressure 1 Vial loading As 20° C. Ambientrequired 2 Cooling down 00:30  5° C. Ambient 3 5° C. hold 03:00  5° C.Ambient 4 Freeze ramp 01:24 5° C. to −37° C. Ambient 5 Freeze hold 06:00−37° C.  Ambient 6 Chamber 00:10 −37° C.  0.2 mbar vacuum 7 Primary16:00 −37° C. to 25° C. 0.2 mbar drying ramp 8 Secondary 24:00 25° C.0.2 mbar drying 9 Vial 25° C. 850 ± 50 mbar stoppering

Secukinumab stability was monitored in the formulations throughdetermination of cake appearance, pH, reconstitution time, residualmoisture by Karl Fischer, aggregates and degradation products bySE-HPLC, impurities by SDS-PAGE under reducing conditions, averagemolecular weight by LLS, degradation products by RP-HPLC and theoreticalactivity by cystamine CEX. Osmolality and viscosity were determinedafter reconstitution 3:1 with water for injection at initial timepoint(Table 13).

TABLE 13 Osmolality and viscosity values for given formulations.Osmolality Viscosity Form Formulation (mOsm/Kg) (mPa*s) 1 270 mM Sucrose452 10.8 2 60 mM Sucrose, 388 10.3 180 mM Mannitol 3 210 mM Sucrose, 44010.5 60 mM Glycine 4 195 mM Sucrose, 421 9.7 45 mM Arginine

Osmolality values were well within the limit of PhEur acceptancecriteria of higher than 240 mOsm/Kg and viscosity results in anacceptable range of 10 mPa*s. The 12 month stability data from samplesstored at real temperature conditions indicated no differences in purityprofile among the formulations with the different stabilizers. Nosignificant difference among formulations was observed in appearance oflyophilisate cake and pH upon storage, however, the formulationcontaining mannitol showed a slightly longer reconstitution time whencompared to the others (6 vs. 3 minutes). Moisture content increasedfrom approximately 0.2% to 0.4% irrespective of formulation (data notshown). Aggregates by SEHPLC increased from approximately 0.9% to 1.4%whereas the degradation products were below the limit of quantification(data not shown). AIN457 average molecular weight remained unchangedafter storage at approximately 155 kDa. Starting levels of total RP-HPLCspecies were approximately 8.5-10% with a significant increase up to14.6% upon 12 months storage at 5° C. (data not shown). It should behighlighted that these levels reached a plateau from 1 month storageonwards. The AIN457 activity by Cystamine CEX was kept at 98-99% (datanot shown). The 6 months stability data from samples stored ataccelerated and stressed temperature conditions revealed that theformulation containing sucrose+mannitol was clearly differentiated fromthe others in terms of the longest reconstitution time (6 min vs. 3min), highest aggregation product levels and generation of RP-HPLCdegradation products upon storage. No significant difference amongformulations was observed in appearance of lyophilisate cake and pH uponstorage. Moisture content increased from approximately 0.2% to 0.6-0.7%irrespective of composition after 6 months storage at 40° C. (data notshown). The sucrose containing formulation showed a slightly loweraggregation level than the other formulations containing, additionally,mannitol, glycine and arginine HCl (5.2% vs. 5.8-6.8% by SE-HPLC). Forall formulations, degradation products were below the limit ofquantification (data not shown). AIN457 average molecular weightremained unchanged after 6 months storage at 40° C. at approximately 160kDa. Total RP-HPLC degradation products were at slightly lower levels inthe stand alone sucrose based formulation or with arginine HCl of up to31.0% and 31.4% when compared to 32.8 and 35.6% in the other twoformulations upon 6 months storage at 40° C. (data not shown). TheAIN457 activity by cystamine CEX was kept at 94-95% (data not shown).

Results from the study showed that the 90 mM sucrose based formulationat 50 mg/mL in 10 mM histidine, 0.02% polysorbate 80, pH 5.8 prior tolyophilization was the most suitable candidate for market formulationcontaining 150 mg/mL AIN457, 30 mM L-histidine buffer pH 5.8, 270 mMsucrose and 0.06% polysorbate 80 after 3:1 reconstitution with 1.0 mL ofwater for injection.

What is claimed is:
 1. A method of treating ankylosing spondylitis (AS),comprising subcutaneously administering to a patient in need thereofabout 150 mg-about 300 mg of an IL-17 antibody or antigen-bindingfragment thereof every four weeks, wherein the IL-17 antibody or antigenbinding-fragment thereof comprises: i) an immunoglobulin variable heavy(V_(H)) domain comprising the amino acid sequence set forth as SEQ IDNO:8 and an immunoglobulin variable light (V_(L)) domain comprising theamino acid sequence set forth as SEQ ID NO: 10; ii) an immunoglobulinV_(H) domain comprising the hypervariable regions comprising the aminoacid sequences set forth as SEQ ID NO:1-3, respectively; and animmunoglobulin V_(L) domain comprising the hypervariable regionscomprising the amino acid sequences set forth as SEQ ID NO:4-6,respectively; or iii) an immunoglobulin V_(H) domain comprising thehypervariable regions comprising the amino acid sequences set forth asSEQ ID NO:11-13, respectively; and an immunoglobulin VL domaincomprising the hypervariable regions comprising the amino acid sequencesset forth as SEQ ID NO:4-6, respectively.
 2. The method according toclaim 1, wherein the IL-17 antibody or antigen-binding fragment thereofis secukinumab.
 3. The method according to claim 2, wherein thesecukinumab dose is about 150 mg.
 4. The method according to claim 3,wherein the patient has active AS.
 5. The method according to claim 3,wherein the patient has moderate to severe active AS.
 6. The methodaccording to claim 3, further comprising administering a non-steroidalanti-inflammatory drug (NSAID) or methotrexate to the patient.
 7. Themethod according to claim 3, wherein the patient previously had aninadequate response to treatment with at least one NSAID.
 8. The methodaccording to claim 3, wherein the patient previously failed to respondto treatment with a disease modifying anti-rheumatic drug (DMARD). 9.The method according to claim 3, wherein, prior to treatment withsecukinumab, the patient had an inadequate response to, had failure to,or was intolerant to treatment with a Tumor Necrosis Factor (TNF)-alphaantagonist.
 10. The method according to claim 2, wherein the secukinumabdose is about 300 mg.
 11. The method according to claim 10, wherein thepatient has active AS.
 12. The method according to claim 10, wherein thepatient has moderate to severe active AS.
 13. The method according toclaim 10, further comprising administering a non-steroidalanti-inflammatory drug (NSAID) or methotrexate to the patient.
 14. Themethod according to claim 10, wherein the patient previously had aninadequate response to treatment with at least one NSAID.
 15. The methodaccording to claim 10, wherein the patient previously failed to respondto treatment with a disease modifying anti-rheumatic drug (DMARD). 16.The method according to claim 10, wherein, prior to treatment withsecukinumab, the patient had an inadequate response to, had failure to,or was intolerant to treatment with a Tumor Necrosis Factor (TNF)-alphaantagonist.
 17. The method according to claim 10, wherein secukinumab iscomprised in a pharmaceutical formulation, wherein said pharmaceuticalformulation further comprises a buffer and a stabilizer.
 18. The methodaccording to claim 17, wherein the pharmaceutical formulation is aliquid pharmaceutical formulation.
 19. The method according to claim 18,wherein the liquid formulation is disposed in a pre-filled syringe,injection pen, or autoinjector, and further wherein the liquidformulation comprises trehalose, histidine buffer, and polysorbate 80.20. The method according to claim 17, wherein the pharmaceuticalformulation is a lyophilized pharmaceutical formulation.
 21. The methodaccording to claim 20, wherein the lyophilized pharmaceuticalformulation is disposed in a vial, and further wherein the lyophilizedpharmaceutical formulation comprises sucrose, histidine buffer, andpolysorbate
 80. 22. The method according to claim 21, wherein thelyophilized pharmaceutical formulation comprises 150 mg/mL secukinumab,30 mM L-histidine, pH 5.8, 270 mM sucrose, and 0.06% polysorbate 80after reconstitution.
 23. A method of treating AS in a patient,comprising administering about 150 mg or about 300 mg of secukinumab bysubcutaneous injection to the patient every four weeks.
 24. A method oftreating active AS in a patient who has responded inadequately toprevious treatment with at least one NSAID, comprising administeringabout 150 mg or about 300 mg of secukinumab by subcutaneous injection tothe patient every four weeks.